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

This is our second update on the litigation (you can see the prior analyses here and here, in addition to a parallel post on our companion blog concerning patent office practice) involving Janssen Biotech, Inc. (“Janssen”), Celltrion Healthcare Co. and Celltrion, Inc. (“Celltrion”), and Hospira Inc. (“Hospira”); but, judging by the course of things, it will not be the last.  There have been several developments since our last post, detailed below.  Most recently, the parties submitted a joint status report detailing the various pending motions.

Our last update occurred shortly after Janssen had filed a new lawsuit against Celltrion and Hospira alleging infringement of U.S. Patent No. 7,598,083 (“the ’083 patent”) under 35 U.S.C. §§ 271(a) and (b), as well as a claim for artificial infringement under 271(e)(2)(C).  Shortly thereafter, the parties agreed to a stipulation that was entered by the Court which, among other things, consolidated the claims for infringement of the ’083 patent into Case No. 17-cv-11008, the “2017 Action.”

Standing Resolved

In January 2017, Defendants alleged for the first time (in what was already at that time a long-running litigation) that Janssen lacked standing to bring suit on the ’083 patent.  See this post.  Specifically, the Defendants argued that the inventors had assigned their rights to a host of Johnson & Johnson companies, and not just Centocor (Janssen’s predecessor).  As such, those entities would be necessary parties, dooming Janssen’s lawsuit.  The Court resolved that question in its October 31, 2017 opinion, ruling that Janssen alone held the rights to the ’083 patent and therefore had standing to bring suit.  The Court began its analysis with the language of the relevant contracts—the inventors’ employment agreements with Centocor, each of which assigned rights in inventions to the “Company.”  But, as Defendants argued, the agreements defined “Company” to include not only Centocor, but also Johnson & Johnson and its other subsidiaries.  The Court was blunt in its view of the agreements, finding them “poorly drafted” and therefore ambiguous.

The Court therefore turned to the parties’ “intent” and the “surrounding circumstances” to determine whether the assignment was to Centocor alone or to the entire Johnson & Johnson family.  Specifically, the Court examined extrinsic evidence, including Janssen’s patent database and several other assignment documents executed between the inventors and Janssen.  Ultimately, the Court found that there was no evidence to rebut the understanding that the agreement was solely between the inventors and Janssen, and therefore found that Janssen alone had standing to bring the lawsuit.  The case continued.

But More Disputes Remain

Although the question of standing has been resolved, there still remain several open motions, including a summary judgment motion that would dismiss Hospira from the case.  To summarize, Celltrion and Hospira have partnered in the marketing of the biosimilar product.  Celltrion has contracted out the manufacture of the allegedly infringing cell culture media.  Janssen alleges that Hospira has joined with Celltrion in a “joint enterprise” and in the process has directly and indirectly infringed the ’083 patent.  Hospira disagrees, contending the theory is unfounded both legally and factually.  Nonetheless, there is no question that the case will proceed with or without Hospira as a defendant.

In addition to the summary judgment motion, the Defendants have moved to strike (what they claim) is a procedurally improper and legally unfounded counterclaim by Janssen.  Specifically, Janssen added a counterclaim under 35 U.S.C. § 271(f)(1), arguing that Defendants have “caused to be supplied” all or a portion of the allegedly infringing cell culture media from the U.S. to Singapore.  That is, whereas the Defendants had purchased the allegedly infringing cell culture media in the U.S., operations changed such that the product is now made (and purchased) in Singapore.  Janssen contends that in the process of moving the operation from the U.S. to Singapore, Defendants committed infringement pursuant to § 271(f)(1).  The Defendants argue that the claim is lacking (on both the facts and the law) and that Janssen raised it in an improper manner.  Therefore, they argue the counterclaim should be stricken.

Finally, the court is set to hear a series of pending Daubert motions and several motions addressing third-party discovery.

***

While the infliximab litigation began in 2014, a final resolution appears unlikely in the near future.

  • U.S. Food & Drug Administration and European Medicines Agency approve first trastuzumab biosimilars
  • U.S. Food & Drug Administration approves a second infliximab biosimilar

As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years.  Global sales for the top nine branded biologic drugs were estimated to total $63 billion in 2016[1].  Competition in the heavily regulated marketplace for these blockbuster therapeutics is expected to substantially impact the pharmaceutical industry and national health systems.  To date, the U.S. has considerably lagged behind Europe’s expansion of biosimilar drug options.  The RAND Corporation estimates that biosimilar products can save the U.S. health system approximately $54 billion over the next decade, as discussed here.

Since 2005, the biosimilar regulatory framework in Europe has been implemented through the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA).  The CHMP provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by the EMA.  Since Sandoz’s somatotropin biosimilar Omnitrope® was first authorized on April 12, 2006, an additional 37 out of 42 applications have been approved in Europe.  Three of the authorizations have been withdrawn post-approval by the marketing authorization holders (Table 1).

The U.S. did not implement a regulatory framework for biosimilar evaluation until after enactment of the Biologics Price Competition and Innovation Act (BPCIA) of 2009.  Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States.  Sandoz’s filgrastim biosimilar Zarxio® received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008.  Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991.   Subsequent to Zarxio®’s approval, only eight other biosimilar drugs have gained U.S. approval to date (Table 2).  As illustrated in the following graph, the EU’s significant head start led to the existent imbalance in the number of biosimilar drugs available in the respective markets.

Currently, sixteen biosimilar applications are under review by the EMA for marketing authorization (Table 3).  As an increasing number of U.S. patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing.  Biosimilars for at least eleven different original biologics are currently navigating the FDA’s biosimilar pathway or are in late stage development (Table 4).

On December 1, 2017, Mylan and Biocon announced that the FDA approved OgivriTM, a trastuzumab biosimilar to Roche’s Herceptin®.  This is the first Herceptin® biosimilar approved by the FDA, and it follows the EMA’s approval of the first Herceptin® biosimilar (Ontruzant®) in November 2017.  No launch date has been set for OgivriTM in the United States.

On December 13, 2017, Pfizer announced that the FDA approved IxifiTM, a infliximab biosimilar to Pfizer’s Remicade®.  This is the second infliximab biosimilar approved by the FDA after Inflectra®’s approval in 2016.  Pfizer currently has no plans to launch IfixiTMin the United States, according to Pfizer spokesperson Thomas Biegi, because Pfizer already markets Inflectra® in the U.S.

On January 15, 2018, the EMA approved MvasiTM, the first bevacizumab biosimilar to Roche’s Avastin in Europe.  The FDA previously approved MvasiTM in September 2017.  MvasiTM is the first product from Allergan’s collaboration with Amgen to receive authorization from the European Commission according to David Nicholson, chief research and development officer at Allergan.

Given biosimilar applicant experience in navigating the EMA process and the EMA’s high authorization rate, the FDA will need to continue to provide useful guidance and streamline the approval process in order to reduce the imbalance.

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated January 24, 2018).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs (CDER list of licensed biologics updated on December 13, 2017).

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines updated on January 4, 2018).

Table 4. Biologics with recent or nearing primary patent expiry in the U.S. that have biosimilars in the regulatory pipeline.

[1] Mullard, Asher. “Bracing for the biosimilar wave.” Nature Reviews Drug Discovery 16.3 (2017): 152-154.

On December 20, 2017, Bristol Myers Squibb Company, Bavarian Nordic, and Enzo Biochem, Inc. filed an amicus brief in support of Amgen’s petition for rehearing en banc. We reported previously that on November 6, 2017, Amgen filed a petition for rehearing en banc of a Federal Circuit panel’s decision vacating a permanent injunction against Sanofi and Regeneron’s Praluent® and remanding the appeal to the district court for a new trial on the defendants’ written description and enablement defenses.

As “innovator biopharmaceutical companies that research targeted treatments for human diseases,” amici expressed concern that the panel’s decision alters existing law under 35 U.S.C. §112 such that it “undermines a reasonable scope of patent coverage” and will cause them to lose their previously-held patent protection.[1] Amici requested that the Court vacate the previous panel’s decision and reconsider the issues.

As previously reported, in its petition Amgen asserted two grounds for rehearing. The amicus brief discussed both of these grounds.

Amici argued that the Federal Circuit panel’s undermining of the “newly characterized antigen rule” set out in Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004) is incorrect because the decision is sound and may only be overturned en banc. Although the panel did not outright overrule Noelle, amici argued that its criticisms and dismissal of the decision leads to the conclusion that it did overturn the decision. Amici also argued that the panel erred by viewing the “newly-characterized antigen rule” as an “antibody exception” to the written description requirement.[2] Instead, the rule is based on antibody science where an antibody genus may be described by the antigen’s structure without the need to describe the multiple representative antibody sequences. Amici asserted that to hold “that a person of ordinary skill in the art does not have possession of the genus of antibodies that bind a well-characterized antigen until she has provided detailed sequence information of multiple representative CDS sequences is an unwarranted extrapolation from organic chemistry.”[3]

Amici then asserted that forty years of precedent demonstrates that an analysis using after-arising embodiments to determine validity based on written description is impermissible. They argued that the rule in In re Hogan, 559 F.2d 595 (C.C.P.A. 1977) makes it clear that an inventor cannot be expected to enable embodiments that were unknown as of the priority date. They further argued that they have relied on this precedent and have operated under this presumption when prosecuting and enforcing their patents.

In addition to addressing the two grounds raised in Amgen’s petition, the brief also emphasized that the panel’s decision will have profound impacts on companies in the molecular medicine field. When researchers seek to obtain genus protection for antibodies, they will now face the burden of having to include a list of the sequences that bind to the antigen. This burden in turn will lead to “never-ending pre-filing actual reductions to practice,” a requirement that small businesses and non-profit organizations cannot afford.[4] Amici argue that even larger companies who can afford the costs will be forced to expend time and resources to create actual reductions to practice when those resources could otherwise go towards other development efforts.

We will continue to provide updates as the case continues.

 

[1] Brief for Bristol-Myers Squibb Co. et al. as Amicus Curiae Supporting Appellees’ Petition for En Banc, Amgen Inc. v. Sanofi, No. 17-1470 (Dec. 20, 2017).

[2] Id. at 5.

[3] Id. at 7.

[4] Id. at 12.