At the urging of Sandoz Inc. (“Sandoz”), the PTAB instituted review of claims 1, 2, and 5-7 of U.S. Patent No. 9,067,992 (“the ʼ992 patent”) on April 3, 2018.  The ʼ992 patent is entitled “Use of TNFα Inhibitor for Treatment of Psoriatic Arthritis,” and is assigned to AbbVie Biotechnology Ltd. (“AbbVie”).  The claims of the ʼ992 patent are generally directed to treating psoriatic arthritis comprising subcutaneous administration of 40 mg of adalimumab every other week. The claims also recite various outcomes associated with the treatment.  In its Petition, Sandoz presented four separate Grounds for unpatentability, and the PTAB instituted review on all four grounds.

Before reaching the Grounds presented by Sandoz, the PTAB first addressed the parties’ respective claim construction positions.  First, Sandoz argued that the preambles to independent claims 1 and 2 are statements of intended use, and therefore are non-limiting.  AbbVie countered that the preambles are limiting because they provide antecedent basis for the claims and are the only parts of the claims that recite psoriatic arthritis and refer to the “said patient,” which is further limited by a dependent claim.  However, the PTAB declined to reach a decision on whether the preambles are limiting, instead concluding that such a determination was unnecessary at this stage.

Although not presented as a claim construction dispute in Sandoz’s petition, Sandoz also asserted that the outcome limitations recited in the various claims are simply statements of intended results that do not convey patentability. Unsurprisingly, AbbVie disagreed.  AbbVie pointed out that the outcome limitations in the claims expressly require particular ACR scores to be achieved following treatment for at least 24 weeks.  Thus, according to AbbVie, the claims require a particular treatment term and a heighted efficacy requirement.  The PTAB agreed with AbbVie and concluded each of the outcome limitations is entitled to patentable weight.

Turning to Ground 1, Sandoz alleged that claims 1, 5, and 6 are anticipated by a publication (Mease 2004) disclosing the results of a clinical trial that evaluated the safety and efficacy of administering 40 mg of adalimumab subcutaneously every other week.  According to Sandoz, the publication describes the same clinical study that was added as an example to the ʼ992 patent specification in a continuation-in-part application.  As a result, the limitations of claim 1, which are based on the patient population and results of the clinical study, are expressly disclosed.  Sandoz further asserted that claims 5 and 6 are anticipated because they recite the clinical outcomes of that study. AbbVie did not contest the Mease 2004 disclosure in its preliminary response.  Instead, AbbVie asserted Ground 1 should be denied because it is irreconcilable with Sandoz’s position regarding the effect of the ACR outcome language. More specifically, AbbVie argued that Sandoz’s position that the outcome language is non-limiting means that Sandoz cannot then rely on those limitations to establish a later effective filing date that makes the Mease 2004 publication available as prior art.  The PTAB sided with Sandoz on this dispute and concluded that Sandoz’s arguments are permissible alternative arguments based on different asserted priority dates.  Moreover, the PTAB also concluded that the limitations are entitled to patentable weight.

Grounds 2-3 alleged the claims are unpatentable as obvious over various combinations of references. Grounds 2 and 3 are substantively similar, and, in fact, have two references in common. In its Preliminary Response, AbbVie did not contest that the references relied on in the Grounds collectively teach the claim limitations.  Instead, AbbVie argued there was no reasonable expectation of success in (1) using adalimumab to treat psoriatic arthritis, or (2) using 40 mg of adalimumab every other week to treat that condition.

In its Petition, Sandoz asserted that psoriatic arthritis and rheumatoid arthritis are closely related diseases that are both mediated by TNF-α.  Sandoz further asserted that both diseases can be treated with the same drugs using the same or similar dosing regimen.  Accordingly, Sandoz argued that prior art disclosing the use of a 40 mg every other week adalimumab dosing regimen for the treatment of rheumatoid arthritis would have rendered use of the same regimen and drug to treat psoriatic arthritis obvious.  AbbVie countered by arguing none of the cited prior art references disclose the use of adalimumab to treat psoriatic arthritis, and, in fact, none of the cited references even discuss a possible connection between adalimumab and psoriatic arthritis. AbbVie similarly argued that disclosures in the cited references regarding the use of other TNF-α inhibitors to treat psoriatic arthritis ignore both the complexities of the disease and the differences between other inhibitors and adalimumab.  According to AbbVie, without this discussion there cannot be a reasonable expectation of success.

The PTAB disagreed by explaining the record indicates that (1) TNF-α was implicated in rheumatoid arthritis and psoriatic arthritis, (2) other TNF-α inhibitors were successfully used to treat both diseases, and (3) based on the success of the other inhibitors, a person of ordinary skill  would have reasonably expected adalimumab to also be successful. Accordingly, the PTAB found a person of ordinary skill would have a reasonable expectation of success in using adalimumab to treat psoriatic arthritis.

Regarding the claimed dosing regimen, Sandoz asserted that a person of ordinary skill would have had a reason to use 40 mg every other week because the prior art discloses that other TNF-α inhibitors were used to treat both rheumatoid and psoriatic arthritis with the same dose and dosing regimen. Consequently, according to Sandoz, a person of ordinary skill would have reasonably expected success in using adalimumab at 40 mg every other week to treat psoriatic arthritis because the prior art taught using adalimumab at the same dose and dosing regimen to treat rheumatoid arthritis. AbbVie argued that Sandoz’s citation to various references describing dosing regimens for other TNF-α inhibitors confirm the uncertainty of dosing.  However, the PTAB found AbbVie’s arguments assumed that the FDA approved dose is the information that would have been relevant to a person of ordinary skill, but that this assumption was counter to the relevant obviousness inquiry.  Accordingly, the PTAB agreed with Sandoz that a person of ordinary skill would have had a reasonable expectation of success in using the claimed dosing regimen based on the current record.

Ground 4 utilizes the same references as Ground 3, but adds a fourth for purposes of claim 7, which depends from claim 2 and adds the limitation that the symptoms reduced by treatment are “progression of structural damage assessed by radiograph.”  Sandoz argued that this limitation is the inherent result of practicing the claimed method or, alternatively, the prior art taught that treating patients with TNF-α inhibitors led to the claimed result.  AbbVie asserted that Sandoz did not put on a sufficient case under either theory and, in particular, Sandoz’s inherency theory was entirely conclusory because it did not cite any data showing that a patient treated with the claimed method would necessarily achieve the claimed result.  However, the PTAB agreed with Sandoz that the claimed result was the inherent outcome of the claimed method based on the current record.  Consequently, the PTAB did not address Sandoz’s alternative theory that the prior art taught the claimed limitation.

We will continue to keep you updated on further developments.

Lately, it has been very difficult to get diagnostic claims allowed without limiting the method steps to very specific components (e.g. reagents, devices, assays, samples, etc.). However, a recent Federal Circuit case suggests that there may be hope for broader diagnostic claims in the future.  In Exergen Corp. v. Kaz USA, Inc., Appeal No. 2016-2315, 2016-2341 (March 8, 2018), the Federal Circuit upheld the district court decision that the claimed diagnostic technique was patent eligible under 35 USC §101.  While the decision is nonprecedential, it shows that not all diagnostic claims are invalid as directed to a natural correlation or law of nature.

Claims 7, 14, and 17 of US Patent No. 6,292,685 (“the ’685 patent”) and claims 17, 24, 33, 39, 40, 46, 49, 60, and 66 of US Patent No. 7,787,938 (“the ’938 patent”) were at issue in Exergen. Claim 14 is representative of the method claims in the ’685 patent and reads as follows:

  1. A method of detecting human body temperature comprising:
    detecting temperature at a forehead through a lateral scan across the
    temporal artery; and
    computing an internal body temperature of the body as a function of
    ambient temperature and sensed surface temperature.

Claim 14 is representative of the method claims in the ’983 patent and reads as follows:

  1. A method of detecting human body temperature comprising making at least
    three radiation readings per second while moving a radiation detector to scan
    across a region of skin over an artery to electronically determine a body
    temperature approximation, distinct from skin surface temperature.

The Federal Circuit considered the two prong test under Alice (Alice Corp. V. CLS Bank Int’l, 132 S. Ct. 2347 (2014) and Mayo (Mayo Collaborative Servs v. Prometheus Labs, Inc., 132 S.Ct. 1298 (2012).  The two prongs are 1) whether the claims at issue contain a patent ineligible concept (law of nature) and 2) whether they contain an “inventive concept” sufficient to transform the claimed abstract idea into a patent eligible application. In other words, if the claims recite only well understood, routine, and conventional activity, they do not constitute an inventive concept.  There was no disagreement that the claims utilized a natural law (correlation between temperature readings from the forehead skin and core body temperature and the calculations used to determine the core temperature based on ambient and skin temperature). The question was whether the additional claimed steps were directed to a novel technique or added an inventive concept so that the claims were transformed into patent-eligible subject matter.  The asserted claims recited at least one of the following steps: 1) moving while laterally scanning across the temporal artery, 2) obtaining a peak temperature reading, and 3) obtaining at least three readings per second.  Though these claim elements were known in the art, they were previously used to detect hot spots indicating injury or tumors or surface temperature differentials.  They were not used to detect arterial temperature beneath the skin.  In addition, the prior art methods did not use the newly determined coefficient for translating measurements taken at the forehead into core body temperature readings. The district court found that there was no evidence that the claimed methods were well understood, routine, and conventional prior to Exergen’s invention. The Federal Circuit agreed, stating that “the inventor determined for the first time the coefficient representing the relationship between temporal-arterial temperature and core body temperature and incorporated that discovery into an unconventional method of temperature measurement” and thus, the method was found patent eligible.

The dissenting opinion stated that the claimed invention measures air temperature and the temperature of forehead skin directly over the temporal artery and then inputs these temperatures into a “heat balance equation,” which is a mathematical representation of the law of nature that governs the relationship between skin, air, and core temperatures.  Devices for measuring temperature while laterally scanning an area were known in the art. Though the specific coefficient was not previously known, the inventors identified this coefficient through empirical testing of the coefficient that governs the relationship between core temperature and the temperature of the skin above the temporal artery.  The dissent concluded that the calculations merely reflect the natural relationship between forehead and core body temperature, and thus the claims lack an inventive concept sufficient to transform them into patent eligible inventions.

It is clear from the dissent that there is still disagreement as to what makes a diagnostic claim patent eligible.  Hopefully this will be cleared up as the Federal Circuit hears more challenges to patent eligibility decisions.  In the meantime, it may be helpful to clearly indicate in the specification why the claimed combination of detection steps is not conventional, and to emphasize any transformations that occur as a result of the diagnostic method.  Specific components used in the method steps should still be disclosed in the specification so that the claims can be limited to these components if the claims continue to be rejected as abstract ideas or natural correlations.

Last week, Mylan N.V. and Biocon Ltd. announced that their jointly-developed insulin glargine biosimilar, Semglee™, received marketing approval from both the European Commission (which applies to all 28 European Union member states) and the European Economic Area member states of Norway, Iceland, and Liechtenstein.[1] Additionally, the Therapeutic Goods Administration approved the biosimilar for use in Australia. While the pharmaceutical partners received U.S. approval for their breast cancer drug Ogivri (the biosimilar Trastuzumab) in December 2017, this is their first co-developed biosimilar to be approved in Europe.[2]

Insulin glargine is a biosimilar of Sanofi’s Lantus™, in which the amino acid sequence of natural human insulin has been genetically modified to improve its absorption, distribution, metabolism, and excretion characteristics in patients with either type 1 or type 2 diabetes.[3] This insulin analog thus provides a drug that is more readily and quickly accepted by the body, with a prolonged duration of activity such that patients may control their blood sugar with just a single dose per day. The approval in Europe and Australia is for a 100 unit/mL 3 mL prefilled disposable pen of the insulin glargine, for application by subcutaneous injection.

While Semglee™ is the third insulin glargine biosimilar to hit the European market (behind Eli Lilly’s Abasaglar™ and Merck’s Lusduna™) and second in Australia (again behind Eli Lilly’s Abasaglar™), the manufacturers hope that the drug will provide an affordable and high quality option for patients and expand the diabetes market on a global scale. The number of people with diabetes in Europe is expected to reach 38 million over the next ten to twelve years and there are nearly 2 million people, and counting, currently living with diabetes in Australia.[4] Thus, as the diabetes pandemic continues to grow at an alarming rate, Mylan and Biocon are entering the lucrative $6 billion global market at the perfect time.[5] The duo plans to launch the product in both Europe and Australia by the end of 2018.

In the same week that Mylan and Biocon announced their success with their insulin glargine biosimilar abroad, the U.S. Food and Drug Administration approved Sanofi’s 900-unit, or 300 unit/mL 3mL, insulin glargine pen, the highest capacity long-acting insulin pen currently on the U.S. market.[6] Sanofi hopes that the new disposable prefilled pen (named Toujeo Max SoloStar), which includes double the dosage of its original SoloStar pen, will ultimately reduce the number of injections needed for some adults with diabetes. With its higher capacity, the pharmaceutical company also expects that the Max SoloStar pen will allow for fewer refills and related copays, depending on the individual’s insurance coverage.[7]

 

[1] Mylan, Biocon Get Approval for Glargine Insulin in Europe, Australia, RTTNews (March 28, 2018), available at http://www.rttnews.com/2876753/mylan-biocon-get-approval-for-glargine-insulin-in-europe-australia.aspx (last accessed April 2, 2018).

[2] Id.

[3] Ambika Basa, Efforts to Develop Generic Versions of Insulin Glargine an Exciting Evolutionary Trend in Diabetes Treatment (March 28, 2018), available at http://www.editiontruth.com/efforts-develop-generic-versions-insulin-glargine-exciting-evolutionary-trend-diabetes-treatment/ (last accessed April 2, 2018).

[4] Viswanath Pilla, We expect roll out of insulin glargine in Europe to start in second half of 2018, says Biocon (March 29, 2018), available at https://www.moneycontrol.com/news/business/companies/we-expect-roll-out-of-insulin-glargine-in-europe-in-second-half-of-2018-says-biocon-2539125.html (last accessed April 2, 2018).

[5] Id.

[6] See Labeling-Package Insert for NDA 206538, Toujeo SoloStar Insulin Glargine Recombinant, available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=206538 (last accessed April 2, 2018).

[7] FDA Approves High-Capacity Insulin Glargine Pen, Healio Endocrinology (March 27, 2018), available at https://www.healio.com/endocrinology/diabetes/news/online/%7Bcec71f19-7d1e-4b27-b4b9-dd7df673ff74%7D/fda-approves-high-capacity-insulin-glargine-pen (last accessed April 2, 2018).

Sanofi-Aventis U.S. LLC, Genzyme Corporation, and Regeneron Pharmaceuticals, Inc. recently scored a victory in their ongoing dispute over a patent that Immunex Corporation claims covers Dupixent®, Sanofi and Regeneron’s anti-IL-4 antibody marketed for treatment of moderate-to-severe eczema. In February, the Patent Trial and Appeal Board (“the Board”) instituted two petitions for inter partes review (“IPR”) (IPR No. 2017-01879 and IPR2017-01884) of Patent No. 8,679,487 (“the ’487 patent”) assigned to Immunex Corp (“Patent Owner”).  Sanofi-Aventis U.S. LLC, Genzyme Corp., and Regeneron Pharmaceuticals, Inc. (“Petitioners”) assert in the first petition (IPR No. 2017-01879) that claims 1–14, 16, and 17 of the ’487 patent are invalid as anticipated by U.S. Patent Application Publication No. 2002/0002132 A1 (“the ’132 Publication”).  The second petition (IPR2017-01884) alleges claims 1-17 of the ’487 patent are invalid as obvious over three prior art references.[1]

The ’487 patent is directed to compositions and methods for treating certain conditions induced by interleukin-4 (IL-4) by administering an IL-4 antagonist.  The sole independent claim requires “[a]n isolated human antibody that competes with a reference antibody for binding to human IL-4 interleukin-4 (IL-4) receptor,” wherein the light and heavy chains comprise SEQ ID NO:10 and SEQ ID NO:12, respectively.  The Petitioners challenged the validity of the ’487 patent, in part, based on experimental evidence provided by their expert declarant showing prior art antibodies inherently competed with reference antibodies described in the ’487 patent.

The IPR petitions are part of a larger legal battle over the ’487 patent.  As previously discussed here, Regeneron, Genzyme, and Sanofi filed a declaratory judgment action in Massachusetts district court in March 2017, seeking a declaration that the ’487 patent is invalid or not infringed.  Immunex counter-sued in the Central District of California.  The Massachusetts case was voluntarily dismissed in May 2017, but the California litigation has continued.

Just after filing their declaratory judgment action, Petitioners also filed a previous IPR petition (IPR No. 2017-01129, filed March 23, 2017), previously reported here.  That earlier petition challenged claims 1–17 of the ’487 patent as being invalid as anticipated by U.S. 2008/0160035 A1 (“the Stevens Publication”).  The Board denied institution of the petition, concluding that the Stevens Publication was not prior art under pre-AIA 35 U.S.C. § 102.

In each of the two IPRs that were ultimately instituted, Immunex argued that the Board should exercise its discretion and deny institution of the follow-on petitions.  Immunex argued the follow-on petitions were directed to the same claims of the same patent and that each of the seven factors applied in General Plastic favor denial.  See Gen. Plastic Indus. Co. v. Kaisha, Patent Tr. & App. Bd. No. IPR2016-01357 (Patent Tr. & App. Bd. Sept. 6, 2017) (Paper 19); see also NVIDIA Corp. v. Samsung Elec. Co., Case IPR2016-00134 (PTAB May 4, 2016) (Paper 9).  Specifically, the framework for exercising discretion to institute follow-on petitions, as applied in General Plastics, includes considering:

  1. whether the same petitioner previously filed a petition directed to the same claims of the same patent;
  2. whether, at the time of filing of the first petition, the petitioner knew of the prior art asserted in the second petition or should have known of it;
  3. whether, at the time of filing of the second petition, the petitioner already received the patent owner’s preliminary response to the first petition or received the Board’s decision on whether to institute review in the first petition;
  4. the length of time that elapsed between the time the petitioner learned of the prior art asserted in the second petition and the filing of the second petition;
  5. whether the petitioner provides adequate explanation for the time elapsed between the filings of multiple petitions directed to the same claims of the same patent;
  6. the finite resources of the Board; and
  7. the requirement under 35 U.S.C. § 316(a)(11) to issue a final determination not later than one year after the date on which the Director notices institution of review.

General Plastic, IPR2016-01357, slip op. at 9-10.

Immunex argued that the Petitioners previously challenged the same claims of the ’487 patent and that they were aware of the cited references asserted in the subsequent petitions before filing the first petition, i.e. IPR No. 2017-01129.  In addition, the Petitioners had already received the Patent Owner’s preliminary response to the first petition and responded to certain arguments at the time of filing the two subsequent petitions.  Immunex finally contended that the Petitioners failed to provide an adequate explanation for why they filed multiple petitions.

However, the Petitioners responded that the petitions could only be filed after experiments were conducted to show the claimed feature, “[a]n isolated human antibody that competes with a reference antibody for binding to human IL-4,” was inherently disclosed in the prior art.  In addition, the Petitioners asserted that the ’487 patent does not specify how to determine whether an antibody “competes with a reference antibody,” as required by the claims, and it was not until November 23, 2016, in a European Patent Office proceeding, that the Patent Owner endorsed two competition assays.  Subsequently, the Petitioners retained experts to complete the experiments needed for the petitions.

The Board found the Petitioners’ reasoning persuasive and decided to institute.  The Board reasoned that the Petitioners did not appear to strategically stage prior art and arguments in multiple petitions.  See General Plastic, IPR2016-01357, slip op. at 17 (“The absence of any restrictions on follow-on petitions would allow petitioners the opportunity to strategically stage their prior art and arguments in multiple petitions, using our decisions as a roadmap, until a ground is found that results in the grant of review.”).  In particular, the Board noted that during prosecution of the ’487 patent, the Examiner did not have the benefit of the Petitioners’ additional experimental evidence relating to competition.  The Board also noted that the competition assay was not an issue in the first petition.  As a result, the Board concluded that the same or substantially the same prior art or arguments were not previously presented to the Office, and the delayed filing to allow time for completion of the additional experiments was reasonable.

As the Board concluded, the present petitions fall under a relatively unique set of circumstances.  However, the reasoning by the Board may provide guidance to parties that similarly find the need to file follow-on petitions in the face of new evidence of invalidity.  This is particularly true in the realm of biologics where many claims require a specific activity of the molecule.  During examination in the Patent Office, many patent applications may escape prior art where the reference describes similar molecules but fails to disclose a specific activity.  This will often require petitioners to retain experts in the field to conduct experiments that are outside the reach of the Patent Office.

We will provide updates as these IPR decisions come to light.

 

[1] Hart et al., Diminished Responses to IL-13 by Human Monocytes Differentiated in vitro: Role of the IL13Rα1 chain and STAT6, 29 EUR. J. IMMUNOL. 2087–97 (1999); Galizzi et al, EP 0 604 693 A1; and Hoogenboom, et al. US 5,565,332.

Biologic drugs are large molecules, such as therapeutic proteins, DNA vaccines, monoclonal antibodies, and fusion proteins, that are typically derived from living cells and used in the treatment, diagnosis, or prevention of disease. Most biologics are produced by genetically engineering living cells to express the therapeutic proteins rather than through traditional chemical synthesis. As proteins are sensitive to the conditions in which they are produced, purified, and stored, biologics are more difficult to chemically characterize and manufacture than small molecule drugs, such that even minor differences in manufacturing processes or cell lines can alter or destroy the desired proteins. Consequently, methods of manufacturing biologics are specialized and critically important to the reliable production of a given biologic.

Patent protection for biologics therefore includes inventive processes for reliably, safely, and consistently manufacturing biologic molecules, in addition to traditional patents such as composition-of-matter patents, formulation patents, and method of treatment patents.  While method of treatment and formulation claims are often attacked on obviousness grounds in view of composition-of-matter-related prior art, method of manufacturing claims in the field of biologics are infrequently challenged given difficulties in identifying invalidating prior art.

On February 15, 2018, in a rare victory for a biosimilar applicant, the Patent Trial & Appeal Board (“PTAB” or “the Board”) cancelled claims 1–17 and 19–24 of Amgen’s U.S. Pat. Number 8,952,138 (“the ’138 patent”), directed to a method of refolding a protein expressed in a non-mammalian expression system in IPR2016-01542.  Only claim 18, which further required that the incubation step of the method be performed under non-aerobic conditions, was not held unpatentable.

During the inter partes review (“IPR”) challenge, Apotex and Amgen also litigated the issues of invalidity and infringement of the ’138 patent in the United States District Court for the Southern District of Florida arising from Apotex’s abbreviated Biologics License Applications seeking permission from the Food and Drug Administration (“FDA”) to market biosimilar versions of pegfilgrastim (Neulasta®) and filgrastim (Neupogen®).[1]  The district court found that Apotex had failed to meet its burden of establishing by clear and convincing evidence that the ’138 patent is invalid for obviousness, but it also found that Amgen had failed to prove that Apotex’s proposed commercial marketing of the two products, pursuant to Apotex’s applications, would infringe the ’138 patent, either literally or under the doctrine of equivalents, as reported here.  On appeal, the Federal Circuit affirmed the district court’s finding of non-infringement, as reported here.[2]  While Amgen argued that the district court had found the claims non-obvious, the Board explained that the standards are different between the two proceedings, and the district court’s decision was not binding on the Board.

Applying the broadest reasonable interpretation standard, the Board construed various claim terms including “protein,” “final thiol-pair ratio,” “redox buffer strength,” “refold mixture,” and “complex protein.”  In resolving a dispute over the construction of “complex protein” the Board grappled with the following competing definitions in the specification: 1) “complex protein, i.e., a protein that (a) is larger than 20,000 MW, or comprises greater than 250 amino acid residues, and (b) comprises two or more disulfide bonds in its native form”; and 2) “complex proteins (e.g., proteins comprising 2-23 disulfide bonds or greater than 250 amino acid residues, or having a MW of greater than 20,000 daltons).”  The Board concluded that the specification set forth the definition of “complex protein” multiple times by using “i.e.” (id est, or “that is”) in contrast to the phrase introduced by “e.g.” (exempli gratia, or “for example”), which the Board concluded “does not indicate a definition.”

The ’138 patent explains that the expression of recombinant proteins in prior art prokaryotic systems was problematic in that the expressed proteins have limited solubility precipitates called inclusion bodies, which are improperly folded proteins.  It states that such complex molecules could not be refolded at high concentrations, i.e., concentrations of 2.0 g/L and higher, with any meaningful degree of efficiency on a small scale, and notably not on an industrial scale.  The ’138 patent’s solution to this problem was a method involving the following steps: (a) contacting the protein with a refold buffer comprising a redox component comprising a final thiol-pair ratio having a range of 0.001 to 100 and a redox buffer strength of 2 mM or greater and one or more of: (i) a denaturant; (ii) an aggregation suppressor; and (iii) a protein stabilizer; to form a refold mixture; (b) incubating the refold mixture; and (c) isolating the protein from the refold mixture.

In assessing motivation to combine, the Board was not persuaded by Amgen’s arguments that a person of ordinary skill in the art would not have combined the references because the secondary reference taught a “chemical approach” to achieve protein refolding at high concentrations, while the primary reference used a “physical approach” by diluting the protein molecules.  The Board found that the primary reference taught using a customizable refolding buffer with a redox buffer option (a chemical approach) and that the secondary reference taught experimenting with concentration ranges to find workable ranges (including dilution).

In assessing reasonable expectation of success, the Board was also not persuaded by Amgen’s arguments that host-cell contaminants would lead one of ordinary skill in the art not to have an expectation of success, as model proteins are not predictive of or applicable to recombinant proteins expressed in mammalian expression systems.  The Board found that the authors of the relied upon exhibit did not come to this conclusion, that Amgen relied on the single worst example in the reference in conflict with the Abstract disclosures of the relied upon exhibit, and extrinsic references introduced by Amgen’s expert insufficiently supported his unpredictability arguments.  Characterizing the determination as “a close call,” the Board concluded that a person of ordinary skill in the art would have looked to solve the problem of refolding proteins at higher concentrations, and would have known that the chemical approach of the secondary reference could apply to the dilution refolding methods of the primary reference.

In attacking the prior art references, Amgen argued that the references did not describe the thiol-pair ratio (“TPR”) and the redox buffer strength (“RBS”) equations disclosed in the ’183 patent’s specification, which Apotex’s expert used to calculate that the prior art taught the same ratios and concentrations of oxidant and reductant as required by the claims.  While characterizing it as an “interesting argument,” the Board rejected Amgen’s argument because “to hold otherwise would eviscerate long-standing legal precedent and simply allow for the patenting of inventions whose only contribution was to quantify into a previously unwritten equation relationships that were discernible to one of ordinary skill in the art from the prior art.” The Board explained that a fact finder must necessarily use these equations to determine whether the prior art taught the ratios and concentrations that are required by the claims.  Accordingly, as the claimed TPR and RBS were found in the prior art, the Board concluded that the combination of the prior art references rendered independent claim 1 obvious.

The Board also rejected Amgen’s argument that refolding of complex proteins as required by dependent claims 9-11 were “extremely difficult” and “challenging,” finding that while refolding proteins is difficult and challenging, the person of ordinary skill in the art is highly skilled and would have recognized that the methods of the prior art references were applicable to those types of proteins.

Finally, in rejecting Amgen’s attempt to antedate a journal publication from 2009 relied on by Apotex’s expert with evidence of earlier-created internal Amgen presentations indicating that a protein code-named “AMG 745” allegedly falls within the scope of the claims, the Board found that the code names of proteins provided no real identification of the type of protein and were insufficient to prove earlier invention.  The Board held that purported antedating documents relied upon to teach a specific type of protein must give a more credible identification of what the protein is in order to be persuasive.

Amgen, in another rarity for a pharmaceutical patent owner, did not assert any objective indicia of non-obviousness.

Thus, in a rare victory for a challenger of method of manufacturing claims by a biosimilar applicant, Apotex successfully convinced the Board that all but one claim of the ’183 patent were unpatentable as obvious over a combination of prior art publications.  Interestingly, by successfully cancelling claims which it was adjudged not to infringe, Apotex may have needlessly cleared the way for competing biosimilar manufacturers.  It remains to be seen if this victory encourages increased challenges of method of manufacturing patents by biosimilar applicants, or if it is chalked up to a rare case involving relatively strong prior art.

 

[1] Amgen Inc. et al. v. Apotex Inc. et al., No. 0:15-CV-61631-JIC/BSS (S.D.Fla.).

[2] Amgen Inc. v. Apotex Inc., No. 2017-1010, 2017 WL 5256264 (Fed. Cir. Nov. 13, 2017).

In October, we reported on a growing number of IPR challenges to Genentech’s U.S. Patent No. 6,407,213 (“the ʼ213 patent”) to Carter. The ’213 patent, “Method for making humanized antibodies,” which Genentech has stated in SEC filings covers technology used in developing the breast cancer drug Herceptin® (trastuzumab), has since been asserted or is otherwise at issue in six  district court litigations.  In addition, some of the pending IPRs have also been instituted for review.

To briefly summarize the IPRs, Samsung Bioepis was the most recent party to file petitions against the ’213 patent, filing two IPRs in September. These petitions moved for joinder with two earlier-filed and pending Pfizer petitions.  In total, ten petitions have been filed, with two by Mylan settled prior to institution, and with two each by Celltrion and Boehringer Ingelheim.

Both Celltrion IPRs were instituted on December 1, 2017. All challenged claims were instituted as to at least one ground in each of the IPRs, with one IPR being instituted as to seven obviousness combinations and the other as to six obviousness combinations and two anticipation references.

The two Pfizer IPRs were also instituted on December 1, 2017. Due to a protective order entered in the case, the decisions instituting the reviews were not released at the time of the institution. Joint statements were later filed in both IPRs stating that neither Institution Decision was requested to remain sealed. In IPR2017-01488, the sealed decision was published on January 11, 2018. All claims challenged were instituted as to at least one ground, and ten originally filed grounds (two anticipation grounds and eight of obviousness) were instituted. The corresponding Samsung Bioepis petition was instituted and the motion for joinder was granted on February 22, 2018.

As to Pfizer’s IPR2017-01489, despite the joint statement that the parties did not request the institution decision to remain sealed, the decision does not appear to have been published, and as such the reasoning of the Board is not available for analysis. However, the corresponding Samsung Bioepis petition was instituted and the motion for joinder was granted on February 22, 2018. This decision, while not reflecting the reasoning of the Board, reflects that at least one ground was instituted as to all claims challenged in the petition, and that all seven asserted grounds (all obviousness grounds) were instituted.

The two Boehringer Ingelheim petitions remain pending.

The ’213 patent has now been asserted or challenged in six complaints, with the first lawsuit filed on October 6, 2017. The first three complaints were between Genentech and Amgen, with Amgen’s proposed biosimilar to Avastin® (bevacizumab) being at issue. The status of those cases has recently been covered here.

The other three lawsuits in which the ’213 patent has been asserted or challenged are related to proposed biosimilars to Herceptin®. The first of these lawsuits began with Genentech alleging infringement of some 40 patents by Pfizer related to its efforts in seeking approval of a Herceptin® biosimilar.

Pfizer provided a copy of its Biologics License Application (“BLA”) on September 5, 2017, following FDA’s acceptance of the BLA for review. Genentech responded with a letter alleging that Pfizer has not provided sufficient manufacturing information, to which Pfizer responded by pointing out the sections in its BLA containing information related to Genentech’s requests, and also providing some additional documents.

Genentech maintained to Pfizer that the provided manufacturing information was insufficient, and provided its initial list of patents to Pfizer on November 3, 2017. On November 17, 2017, Pfizer provided Genentech with its notice of commercial marketing. On the same day, Genentech filed suit. In its complaint, Genentech stated that Pfizer had not provided its detailed statement regarding the non-infringement and invalidity of the patents in Genentech’s list.

In its answer filed on January 10, 2018, Pfizer noted that it provided its detailed statement on January 2, 2018. In its counterclaims, Pfizer further alleged that it had complied with the requirements of the Biologics Price Competition and Innovation Act (“BPCIA”), while Genentech’s filing of a suit before Pfizer’s detailed statement was due was premature and therefore a violation of the BPCIA.

Specifically regarding the ’213 patent, in addition to allegations that the ’213 patent was invalid and not infringed, Pfizer alleged in greater detail that the ’213 patent was unenforceable due to the misrepresentation of a prior art reference made to the Examiner during prosecution in order to overcome a rejection based on that prior art reference.

The suit is pending, with the most recent action being a Joint Status report filed on February 12, 2018.

The other two Herceptin®-related suits involve Celltrion and Teva’s efforts towards a Herceptin® biosimilar, the first of which involves Celltrion and Teva filing as co-plaintiffs for declaratory judgment of non-infringement, invaldity, and unenforceability of 38 patents, including the ’213 patent, on January 11, 2018. We have previously reported on this suit. Since our previous report, an amended complaint was filed on February 8, 2018, with a stipulation filed the same day extending the time to answer to March 1, 2018.

A motion to dismiss appears to have been filed on February 28 (a motion to file under seal was filed the same day as the motion, while the unredacted motion was inadvertently publically accessible and has since been removed). In a redacted version of the motion attached to Genentech’s motion to file under seal, Genentech alleges that the BPCIA preserves Genentech’s right to sue first as the innovator, and that Celltrion and Teva’s declaratory judgment action is barred.  Responses are due March 14, 2018, and a motion hearing is set for April 4, 2018.

On January 12, 2018, Genentech responded with its own suit for infringement of 40 patents against Celltrion and Teva. A stipulation in this case has extended the time to answer to April 16, 2018. A response from Celltrion and Teva has yet to be filed.

Sandoz’s request for inter partes review (“IPR”) of U.S. Patent Numbers 9,512,216 (“the ’216 patent”) and 8,802,100 (“the ’100 patent”) was denied by the Patent Trial and Appeal Board (“the Board”) on the grounds that Sandoz did not show that the patents were likely unpatentable.  The decisions not to institute an IPR of either patent were entered on February 9, 2018.

The Board’s decision denying the request for review of the ’216 patent indicates that a threshold issue was whether there was an adequate showing that the Humira® package insert is prior art.  In an IPR, the patent claims may only be challenged based on prior art consisting of patents and printed publications.

Sandoz asserted that all of the claims in the ’216 patent were obvious over the combination of the Humira® package insert; psoriasis press release; Aulton ed., 2d ed.2002, Pharmaceutics: The Science of Dosage Form Design; Weinstein & Gottlieb eds, 2d ed. 2003, Therapy of Moderate-to-Severe Psoriasis; and in view of Ortega et al., Infliximab is Effective in the Treatment of Resistant Psoriatic Arthritis & Skin Psoriasis: A Clinical & MRI Study, Rheumatology 2002.  The key issue was whether the package insert was sufficiently accessible to the public before the effective filing date of the ’216 patent. MPEP §2128 states that a reference is considered to be a printed publication if “upon a satisfactory showing that such document has been disseminated or otherwise made available to the extent that persons interested and ordinarily skilled in the subject matter or art, exercising reasonable diligence, can locate it.” In re Wyer, 655 F.2d 221, 210 USPQ 790 (CCPA 1981) (quoting I.C.E. Corp. v. Armco Steel Corp., 250 F. Supp. 738, 743, 148 USPQ 537, 540 (SDNY 1966)).  Sandoz argued that Humira® was approved in December 2002, and that the package insert included the language “Issued: December 2002” and contained the date “December 20, 2002” in the header.    In addition, Sandoz pointed out a December 31, 2002 letter from the FDA approving the biologics license application.  However, Sandoz did not point out any source identifying information from the FDA, a publication date, or any other evidence indicating when the package insert or the information in the package insert became publicly available.

AbbVie responded that Sandoz did not sufficiently establish that the insert was publicly accessible in December 2002. The December 31, 2002 FDA letter stated that Humira® “will be marketed in 40 gm/0.8 mL single use” vials and syringes.  The Board interpreted the language “will be marketed” as an indication that the Humira® drug product was not yet marketed or available to the public.  The Board concluded that there was not sufficient evidence that the Humira® package insert was disseminated or publicly accessible before the April 9, 2004 priority date of the ’216 patent, and thus Sandoz failed to demonstrate a reasonable likelihood that the package insert was a printed publication for purposes of 35 USC §§102(b) and 311(b).  Since the insert was the only cited reference which disclosed subcutaneously administering 40 mg of adalimumab every other week, the Board was not persuaded that the record established a reasonable likelihood that Sandoz would prevail at trial as to the challenged claims.

Sandoz also requested review of all of the claims in the ’100 patent.  Sandoz asserted that all of the claims in the patent were obvious over the combination of Salfeld (U.S. Patent No. 6,090,382); van de Putte et al., Efficacy of the Fully Human Antibody D2E7 in Rheumatoid Arthritis, 42 Arthritis & Rheumatism S400 (1999); Barrera et al, Effects of Treatment with a Fully Human Anti-Tumor Necrosis Factor a Monoclonal Antibody on the Local & Systemic Homeostasis of Interleukin 1 and TNFa in Patients with Rheumatoid Arthritis, 60 ANN. RHEUM. DIS. 660-69 (2001); Remington: THE SCIENCE & PRACTICE OF PHARMACY (Alfonso R. Gennaro et al. eds, 20th ed. 2000); and Lam (U.S. Patent No. 6,171,586).  Sandoz argued that Salfeld disclosed “stable, buffered, subcutaneously-injectable aqueous D2E7 formulations containing a polyol, and a surfactant,” thereby providing a roadmap to the challenged claims.  Salfeld did not disclose the antibody concentration or the surfactant type and concentration.  Van de Putte was cited as disclosing the antibody concentration, Remington was cited as disclosing the surfactant, and Lam was cited as disclosing the concentration of the surfactant.  The Board was not persuaded by Sandoz’s arguments, finding that the evidence “indicates that the art of antibody formulation was unpredictable in August 2002,” and that no evidence had been provided showing that one skilled in the art would have a reason to combine the cited prior art with a reasonable expectation of success in preparing a stable, liquid formulation with the concentration of antibody and surfactant recited in the claims.  The Board pointed out that it is not clear that the reference relied on as disclosing the antibody concentration (van de Putte), discloses a stable liquid formulation or a lyophilized formulation.

AbbVie pointed out that all commercially available high-concentration antibody formulations available in August 2002 were lyophilized, while the available liquid formulations contained low antibody concentrations.  AbbVie also pointed out evidence that one skilled in the art would not have used teachings regarding lyophilized formulations to prepare stable, liquid formulations, as lyophilized formulations do not have the same stability issues as high concentration liquid antibody formulations. In addition, AbbVie argued that references which disclose formulations containing antibodies other than D2E7 do not provide a reasonable expectation of success for preparing a D2E7 formulation. Abbvie further argued there is a high degree of unpredictability in the antibody formulation art and thus a formulation for a specific, stable, high concentration, liquid antibody formulation cannot be applied to a different antibody with a reasonable expectation of success.  In addition, Abbvie asserted structural differences between different proteins do not allow stabilization strategies to be universally applied.  The Board concluded that Sandoz did not establish a reasonable likelihood of prevailing in its assertion that the claims in the ’100 patent would have been obvious, and therefore did not institute review.

Humira is the best-selling biologic in the world and AbbVie’s more than 100 patents covering Humira-related technology will likely face more challenges from generic competitors.  However, for now, AbbVie’s strategy of obtaining numerous patents covering every aspect of the Humira technology is successfully keeping competitors out of their $16 billion a year market.

Mumbai-based pharmaceutical manufacturer Lupin recently received FDA approval for its generic version of Roche’s Tamiflu® (oseltamivir phosphate), one of the most popular antivirals prescribed for relief from the influenza virus. The active ingredient is indicated for the treatment of acute, uncomplicated influenza A and B in patients two weeks of age or older who have been symptomatic for no more than forty-eight hours. The drug comes in capsule form in strength amounts of 30 mg, 45 mg, and 75 mg.[1]

This FDA approval comes near the end of a particularly dangerous flu season, which scientists consider to rival the swine flu pandemic of 2009.[2] The latest report from the Centers for Disease Control and Prevention (“CDC”) in the first week of February notes that 7.7% of reported patients visiting hospitals nationwide -nearly 1 out of every 13 hospital patients- have come in with flu-like symptoms, including a temperature of 100°F or greater and cough and/or sore throat.[3] This is well above the national baseline of 2.2%.[4] The report further explains how there has been a significant increase in deaths resulting from the virus, especially in vulnerable populations such as children and the elderly, with over 60 reported pediatric deaths thus far across the country.[5]

As the flu vaccine has only proven to be about 30% effective against this year’s most prevalent virus strain, prescriptions of treatments like Tamiflu® are on the rise.[6] In a market currently worth over $500 million a year in U.S. sales, Lupin is right on time for the party, joining pharmaceutical competitors Natco, Macleods, Nesher, Alvogen, and Amneal, who also received FDA approvals for generic oseltamivir phosphate capsules and/or oral suspensions in 2016 and 2017.[7] This new competition is finally leveling the playing field with Roche, who has dominated the market since obtaining FDA approval for the Tamiflu® oral capsules and suspensions in 1999 and 2000, respectively.[8]

Notably, Lupin should face little to no opposition from Roche in bringing the generic to market. While Roche, in addition to Genentech and Gilead Sciences, the collective owners of U.S. Patent No. 5,763,483 for Tamiflu®, sued Lupin in a Maryland federal court in 2015 for patent infringement based on an intent to market the drug before the patent expires in 2021, the parties were able to come to a settlement agreement and the case was dismissed in May of 2016.[9]

 

[1] FDA Drug Approval for ANDA 208348, available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208348 (last accessed on February 12, 2018).

[2] Mike Stobbe, This Year’s Flu is Now as Bad as the 2009 Sine Flu Epidemic, CDC Says, TIME, available at http://time.com/5143232/cdc-flu-epidemic/ (last accessed on February 12, 2018).

[3] Centers for Disease Control and Prevention, 2017-2018 Influenza Season Week 5 ending February 3, 2018, available at  https://www.cdc.gov/flu/weekly/#S6 (last accessed on February 12, 2018).

[4] Id.

[5] Id.

[6] Centers for Disease Control and Prevention, Vaccine Effectiveness- How Well Does the Flu Vaccine Work, available at https://www.cdc.gov/flu/about/qa/vaccineeffect.htm (last accessed on February 12, 2018).

[7] FDA Approvals for Oseltamivir Phosphate, available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process (last accessed on February 12, 2018).

[8] Id.

[9] Gilead Sciences, Inc. et al. v. Lupin Pharmaceuticals, Inc., No. 1-15-cv-02793 (D. MD May 12, 2016).

Last week, the Federal Circuit affirmed a lower court’s dismissal of AbbVie’s complaint seeking declaratory judgment of invalidity of U.S. Patent No. 6,248,516 (“the ’516 patent”) owned by Astra Zeneca subsidiary MedImmune.  AbbVie brought this declaratory judgment action in June 2016 in the hopes of ending its royalty obligations to MedImmune.

The Fed. Circuit’s decision on appeal from the U.S. District Court for the Eastern District of Virginia establishes that a party may not seek declaratory judgment to obtain piecemeal adjudication of subsidiary issues that do not resolve the overall dispute.

The declaratory judgment action is related to a development and licensing agreement initiated in 1995 that led to the antibody known as adalimumab.  Adalimumab is the active ingredient in the blockbuster drug Humira®.  As we reported previously, Humira® generated over $16 billion USD in 2016, becoming the world’s best-selling drug.  The agreement allowed AbbVie to practice a number of patents, including the ’516 patent, but required AbbVie to pay royalties on related sales until the later of fifteen years from the date of First Commercial Sale or the expiration date of the last patent to expire amongst the specified patents under the agreement (i.e. the expiration of the ’516 patent).  Therefore, under the agreement, royalties would be paid to MedImmune until January 2018 or June 2018, respectively.  AbbVie asserted that a declaration of the ’516 patent’s invalidity would be an expiration of the patent for the purpose of the agreement, thereby ending its royalty obligations.

The district court dismissed AbbVie’s complaint for two reasons: (1) AbbVie did not practice the ’516 patent, and therefore lacked standing since it could not be subject to patent infringement; and (2) even in the event AbbVie had standing, the court declined to use its discretionary declaratory judgment jurisdiction since the British government jointly owns the patent and the agreement is governed by British contract law.  Accordingly, the invalidity question would not likely resolve the parties’ underlying dispute in view of concerns about foreign law and sovereign immunity.

The Fed. Circuit disagreed with the district court over its holding that it lacked declaratory judgment jurisdiction.  The court reasoned that even in the absence of patent infringement, it should look to the “‘character of the threatened action’ that the declaratory judgment defendant ‘might have brought.’”  Specifically, the contractual obligations under the 1995 agreement would turn on the expiration and/or validity of the ’516 patent.  The court opined that “[i]f properly presented, such a contractual dispute could confer declaratory judgment jurisdiction.”

However, in the instant case, AbbVie sought out declaratory judgment of invalidity in regard to the ’516 patent, rather than its contractual obligations.  The court noted that AbbVie has no other pending litigation in American or British courts that could resolve the contractual dispute.  Accordingly, the court held that AbbVie cannot establish declaratory judgment jurisdiction over invalidity, reasoning that it is an open question as to how the British courts would view the invalidity of ’516 patent in relation to patent expiry under the agreement.

On February 2, 2018, U.S. District Judge George H. Wu granted Genentech’s motion to dismiss a complaint brought by Amgen in the Central District of California seeking a declaratory judgment of non-infringement, invalidity, and unenforceability of twenty-seven patents related to Genentech’s cancer treatment biologic, Avastin® (bevacizumab).[i]

Judge Wu issued a tentative decision on January 11, 2018, stating he would grant the motion to dismiss, but stayed that decision until a determination was made in two related Delaware cases on Amgen’s motions to transfer venue to the Central District of California.[ii] The Delaware court denied Amgen’s motions to transfer venue on January 22, 2018.[iii]

Judge Wu granted the motion to dismiss based on the court’s “broad discretion under the Declaratory Judgment Act, including [his] concerns that Amgen’s suit in [the Central District of California] was anticipatory and that the concurrent proceedings in Delaware would lead to duplicative litigation.” He also based his decision on the reasons provided in the tentative decision, where he noted that he was declining to hear Amgen’s case because Amgen had not properly completed the negotiation process required by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”). He stated that he would decline “to hear a case where Amgen effectively attempted to bypass the BPCIA’s scheme for negotiations and eventual litigation.”

The dispute arose over Amgen’s attempts to seek approval from the FDA to market a biosimilar of Avastin®. The FDA approved Amgen’s Mvasi™ (bevacizumab-awwb) as a biosimilar to Genentech’s Avastin® on September 14, 2017.[iv] On October 6, 2017, Amgen provided its notice of commercial marketing to Genentech and immediately filed the declaratory judgment action in the Central District of California. That same day, Amgen reached out to Genentech to continue the final patent exchange procedures as required for the first phase of patent litigation under the BPCIA. Genentech learned of Amgen’s declaratory judgment action and immediately filed a lawsuit in Delaware alleging infringement of twenty-four of the twenty-seven Avastin®-related patents at issue in the declaratory judgment action. The parties completed the BPCIA’s required negotiation process on October 13, 2017, and Genentech brought its “first phase” lawsuit in Delaware on October 18, 2017, asserting infringement of twenty-five of the twenty-seven patents and alleging that Amgen failed to comply with its statutory obligations under the BPCIA. Genentech’s two Delaware cases have been consolidated. Amgen filed a motion to dismiss for failure to state a claim and for lack of subject matter jurisdiction, which is currently pending before the Delaware court.

 

[i] Amgen Inc. v. Genentech, Inc., Case No. 2:17-cv-07349 (C.D. Cal. Feb. 2, 2018) (Docket No. 63).

[ii] Amgen Inc. v. Genentech, Inc., Case No. 2:17-cv-07349 (C.D. Cal. Feb. 2, 2018) (Docket No. 56).

[iii] See Genentech, Inc. v. Amgen Inc., Civ. No. 17-1407-GMS (D. Del. Jan 22, 2017) (Docket Nos. 58 & 59) and Genentech, Inc. v. Amgen Inc., Civ. No. 17-1471-GMS (D. Del. Jan 22, 2017) (Docket No. 57).

[iv] https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm576112.htm