As we previously reported, earlier this year the Federal Circuit affirmed a district court’s finding that Sandoz’s ZARXIO filgrastim biosimilar and proposed pegfilgrastim biosimilar do not infringe Amgen’s patents. The patents-at-issue were Amgen’s U.S. Patent Nos. 8,940,878 (“the ’878 patent”) and 6,162,427 (“the ’427 patent”). The ’872 patent is directed towards methods of purifying proteins expressed in non-mammalian systems in both non-native soluble and non-native insoluble forms. The ’427 patent is directed towards methods of treatment involving administering a hematopoietic stem cell mobilizing-effective amount of G-CSF before administering chemotherapy to the patient. The District Court for the Northern District California construed the claims of both patents and granted summary judgment of non-infringement of claim 7 of the ’878 patent in favor of Sandoz. Amgen later appealed the decision. The Federal Circuit concluded that there was no infringement and that Amgen could not succeed on its doctrine of equivalents theory, explaining that “[t]he doctrine of equivalents applies only in exceptional cases and is not simply the second prong of every infringement charge, regularly available to extend protection beyond the scope of the claims.” See Amgen Inc. v. Sandoz Inc., 923 F.3d 1023, 1029 (Fed. Cir. 2019).

In June, Amgen filed a petition for rehearing en banc. Amgen argued that the Federal Circuit established a bright line rule that the doctrine of equivalents only applies in exceptional cases and that such a rule is contrary to both Supreme Court precedent and the Federal Circuit’s prior precedent. Amgen argued that the panel decision “represents a profound change in the law that appears to impose an equitable standard explicitly rejected by the Supreme Court.” Pet. at 3. Citing several Supreme Court cases, Amgen argued that the idea that the doctrine of equivalents is available in all cases and is assessed without regard to equities is consistent with over 150 years of Supreme Court precedent. Pet. at 5. Amgen went on to state that under the correct doctrine of equivalents standard for assessing infringement, the Federal Circuit erred in affirming the district court’s decision.

On September 3, 2019, the Federal Circuit partially granted Amgen’s petition. The Federal Circuit ordered that the petition is granted such that the portion of the panel’s opinion stating that the doctrine of equivalents “applies only in exceptional cases” is removed. The Federal Circuit denied the rest of the petition, thereby upholding the panel’s ruling of noninfringement. The Federal Circuit did not provide any reasoning in its order but its decision demonstrates that the prior panel was incorrect in establishing a bright-line rule that the doctrine of equivalents only applies in exceptional cases.

The U.S. Food and Drug Administration (FDA) and the E.U. European Medicines Agency (EMA) announced that Slovakia has beeen added to a mutual recognition agreement (MRA) regarding good manufacturing practice (GMP) inspections in the European Union.  Slovakia was the last of the 28 member states of the European Union to be recognized as capable of conducting manufacturing facility inspections which meet FDA requirements. The MRA allows the FDA and the EMA to use inspection reports and other related information obtained by the other agency during manufacturing facility inspections. Either agency can require additional inspections or other actions as necessary to protect the public. The recognition of European drug regulatory authorities as capable of conducting inspections which meet FDA requirements is part of the implementation of the amended Pharmaceutical Annex to the 1998 U.S. – E.U. MRA.

Medicinal products approved for use in the U.S. can be manufactured or contain ingredients manufactured in other countries.  Since all drugs approved in the U.S. must comply with U.S. regulations, FDA inspects both foreign and domestic manufacturing facilities on a regular basis. Prior to implementation of the MRA, both the FDA and the EMA conducted inspections of the same manufacturing facilities and pharmaceutical companies were required to carry out batch testing for products imported into the U.S. even though similar testing had already been carried out in other countries. The full implementation of the MRA will avoid duplication of facility inspections in Europe and the U.S. which will allow the agencies to direct more resources to inspections in other countries. In addition, costs should be reduced for pharmaceutical manufacturers since batch testing for products imported into the U.S. will be waived when such testing has been carried out in a member state of the European Union.

Human drugs and biologics are encompassed by the MRA , however, specified products are still being assessed. Veterinary medicines are still being assessed with a decision expected by December 15, 2019. A decision regarding human vaccines and plasma derived medicines is expected by July 15, 2022; and a decision on products intended for use in clinical trials is expected to be made at an unspecified date in the future.  Products which are excluded from the MRA include human blood and plasma, human tissues and organs, veterinary immunologicals and medicines based on genes, cells or tissue engineering.

The MRA will facilitate market access, encourage harmonization of compliance standards, reduce duplication of inspections and reduce costs by waiving re-testing of products upon importation.

On July 11, 2019, more than 110 House Democrats wrote a letter to U.S. Trade Representative Robert E. Lighthizer expressing strong opposition to provisions in the United States-Mexico-Canada Agreement (USMCA) trade agreement, including the provision setting a minimum of 10 years of marketing exclusivity for biologic drugs.

As discussed here, in the United States, the Biologics Price Competition and Innovation Act (“BPCIA”) already provides for 12 years of data exclusivity for new biologics, exceeding the minimum 10 years under the USMCA. Thus, the USMCA does not purport to extend biologics monopolies in the United States, but instead requires Canada and Mexico to adopt a more similar exclusivity period.  However, two of the signatories to the letter, Representatives Jan Schakowsky, D-Illinois and Rosa DeLauro, D-Connecticut, introduced HR 3379, the Price Relief, Innovation, and Competition for Essential Drugs (PRICED) Act, in June 2019, seeking to shorten the exclusivity period for brand name biologic drug products from 12 years to only 5 years.

The House members argue that the current provisions in the USMCA “would keep drug prices out of reach for patients by increasing and locking in 10 years of marketing exclusivity for brand biologics, expanding the scope of brand biologics eligible for protection, and making it easier for brand-name drug companies to extend their monopolies through additional patents, patent extensions, and other forms of patent ‘evergreening.’”  The signatories warn that the opposed provisions “limit Congress’ ability to adjust the biologics exclusivity period, instead locking the US into policies that keep cancer and other drug prices high.”

The legislators request revisions to the access to medicines provisions in the USMCA to make them consistent with the Bipartisan Agreement on Trade Policy of May 10, 2007 struck during the George W. Bush Administration, summarized here.  That Agreement identified the following particular intellectual property elements:

  • Clarification that the period of protection for test data for pharmaceuticals by developing country FTA partners will generally not extend beyond the period that such protection is available for the same product in the United States, coupled with a provision that will encourage our partners to process marketing approval applications for innovative drugs in a timely manner.
  • Clarification that developing country FTA partners may implement exceptions to normal rules for protecting test data if necessary to protect public health.
  • A more flexible approach, for developing country partners, to restoring patent terms to compensate for processing delays. This flexibility is accompanied by new provisions stipulating that trading partners will make best efforts to process patent and marketing approval applications expeditiously.
  • More flexibility in terms of the types of procedures that developing country partners may implement to prevent the marketing of patent-infringing products.
  • Integration within the intellectual property chapter of a recognition that nothing in the chapter affects the ability of our FTA partners to take necessary measures to protect public health by promoting access to medicines for all, and a statement affirming mutual commitment to the 2001 Doha Declaration on the TRIPS Agreement and Public Health.

Notably, it has been the U.S. Trade Representative’s policy to negotiate trade agreements based on United States laws including the 12 year exclusivity period for biologic drug products.  Accordingly, the USMCA’s 10 year period appears to be a compromise reached with Canada’s current 8 year period.  Nevertheless, the legislators oppose the provision because the USMCA will limit Congress’ ability to reduce the biologics data exclusivity from 12 years to less than the 10 years required by the USMCA.

Given that the USMCA is a trade agreement seeking to protect U.S. trade interests including sales by U.S. pharmaceutical companies into Canada and Mexico, and not an agreement seeking to lower prescription drug prices in the United States, it is unlikely that presupposed benefits of removing the language will outweigh the more tangible benefits of extending biologic product manufacturers’ exclusivity periods in the Canadian and Mexican markets.

Canada implemented its patent term extension program, the Certificate of Supplementary Protection (CSP) framework, on September 21, 2017.  The CSP regime is beneficial to qualifying pharmaceutical product developers because it can add up to two additional years of patent protection.  Notably, CSP is not as beneficial as other major jurisdictions, which generally allow up to five years of patent term extension. The purpose of the CSP regime is, in part, to compensate pharmaceutical product innovators for patent term lost while waiting for regulatory approval in Canada in accordance with the Comprehensive Economic and Trade Agreement (CETA) with the European Union.  Due to CSP’s strict timing requirements, multi-national pharmaceutical companies must pay particular attention to regulatory filing dates for new drug applications in Canada and in other jurisdictions, as well as deadlines for filing CSP applications in Canada.

To be eligible for a CSP, the applicant must obtain an eligible patent, obtain approval by Health Canada via a Notice of Compliance (NOC), follow strict timing requirements, meet various restrictions on claim scope, and pay an application fee.[1]

A patent is eligible if it includes at least one claim directed to a medicinal ingredient or combination of all the medicinal ingredients in a drug, a medicinal ingredient or combination of all the medicinal ingredients obtained by a specified process (product by process claim), or a use of the medicinal ingredient or combination of all the medicinal ingredients in a drug. Pure process claims or formulation claims are considered to not protect the medicinal ingredient or combination of medicinal ingredients per se, and are not considered eligible for a CSP.  Thus, the CSP framework is also more restrictive in terms of the types of claims that are eligible for CSP compared to other major jurisdictions.[2]

The NOC must be the first authorization issued in Canada with respect to the medicinal ingredient or the combination of medicinal ingredients. To be considered the first authorization, the medicinal ingredient or combination must include more than “prescribed variations” from a prior authorization.  Specifically, the medicinal ingredient cannot be: (1) esters, salts, complexes, chelates, clathrates, or other non-covalent derivatives; (2) enantiomers or mixtures of enantiomers; (3) solvates or polymorphs; (4) in vivo or in vitro post-translational modifications; or 5) any combination of (1)-(4), of a previously authorized medicinal ingredient.  As such, the Canadian list of “prescribed variations” is more broadly defined than those in other major jurisdictions.

The prescribed variations list will be particularly restrictive for biosimilars and biobetters compared to other jurisdictions. For example, the human biologic product GAZYVA (obinutuzumab) received Patent Term Extension (“PTE”) of 946 days in the United States.[3] GAZYVA is a leukemia drug marketed by Roche which has a significantly better clinical efficacy than Roche’s earlier drug Rituxan. Although both drugs target the same protein, GAZYVA has a modified glycosylation pattern, making the antibody-tumor complex more recognizable by macrophages. In the United States, only salts and esters are expressly excluded variations.[4] However, GAZYVA would not be eligible for CSP because glycosylation modifications are an excluded variation under Canada’s list of prescribed variations.

For applicants seeking drug approval in the European Union, any member country of the European Union, the United States, Australia, Switzerland or Japan, the applicant must file for new drug approval with Health Canada no later than 12 months after filing in these countries.[5]  While, the 12 month filing requirement for the new drug submission may incentivize pharmaceutical developers to file new drug applications in Canada sooner, the 12-month filing requirement will add new complexities and considerations for multi-national pharmaceutical companies. For example, filing for approval in another country too soon would cause an applicant to forfeit patent term extension in Canada.  Additionally, the CSP application must be filed within 120 days following the issuance of the NOC or within 120 days of the patent’s grant date, whichever occurs later.

To date, 42 applicants have filed CSP applications. Of those, 29 have been issued a CSP, 7 have been refused, and 6 are pending.[6]  Notably, application 900011 for Rebinyn® (Coagulation Factor IX (recombinant), glycoPEGylated) was rejected because it only varied from the authorized medicinal ingredient by post-translational modifications, namely pegylation and different glycosylation patterns. In Canada, the patent for Rebinyn® (CA 2,462,930) will expire August 2022, while U.S. patent 7,138,371 received 381 days PTE and is not expected to expire until November 2023. [7]

Overall, the CSP framework adds complex new variables for pharmaceutical companies to consider when developing and executing global regulatory strategies.  It also creates new considerations when implementing patent strategies, e.g., targeted claim drafting and timing of patent prosecution procedures to ensure eligibility and maximization of patent term extension under the CSP framework.  To take advantage of the new framework, multi-national pharmaceutical companies will need to update regulatory and patent filing procedures as well as increase communications between regulatory personnel, in house patent portfolio managers, and outside patent prosecution counsel.

[1] See Guidance Document – Certificates of Supplementary Protection, Gov’t Can., https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/register-certificates/certificate-supplementary-protection-regulations.html#a228 (last modified Mar. 28, 2019).

[2] See, e.g., 35 U.S.C. § 156(a) (“The term of a patent which claims a product, a method of using a product, or a method of manufacturing a product shall be extended in accordance with this section from the original expiration date of the patent . . . .”).

[3] Letter from Mary C. Till, Senior Legal Advisor, USPTO, to Catherine M. Polizzi, Morrison & Forester LLP (Nov. 20, 2017) (enclosing a certificate under 35 U.S.C. § 156 extending the term of U.S. Patent No. 6,602,684 for a period of 946 days).

[4] 35 U.S.C. §156(f)(2)(B).

[5] Previously, applicants were extended an extra 12-month grace period for a total of 24 months. However, this only applied if the CSP application was filed before September 21, 2018, the first anniversary of the day on which section 59 of the CETA Implementation Act comes into force.

[6] See Certificates of Supplementary Protection (CSP) and Applications, Gov’t Can., https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/register-certificates.html (last modified June 18, 2019).

[7] See Certificates of Supplementary Protection (CSP) and Applications, supra note 6; Determination of Regulator Review Period for Purposes of Patent Extension; REBINYN, 83 Fed. Reg. 54112 (Oct. 26, 2018).

In a recent precedential opinion[1], the Federal Circuit rejected arguments by Amgen that a single step purification process used by Sandoz for its G-CSF biosimilar infringed claims of Amgen’s patent describing a multistep purification procedure for proteins expressed in a non-mammalian system.

In this case, the Federal Circuit explained that the doctrine of equivalents is not a second prong to patent infringement that enables patent holders to extend the scope of their claims, but rather applies only to exceptional cases.

The appeal stems from two decisions out of the Northern District of California related to patent infringement actions brought by Amgen, Inc. and Amgen Manufacturing, Ltd. (“Amgen”) against Sandoz Inc., Sandoz International Gmbh, and Sandoz Gmbh (“Sandoz”).  The appeal centers on the lower court’s grant of summary judgement of noninfringement of claim 7 of Amgen’s U.S. Patent No. 8,940,878 (“the ’878 patent”) and claim 1 of Amgen’s U.S. Patent No. 6,162,427 (“the ’427 patent”) by Sandoz’s filgrastim biosimilar and its proposed pegfilgrastim biosimilar.

Amgen’s primary patents covering its filgrastim and pegfilgrastim biologics (marketed as Neupogen® and Neulasta®, respectively) expired in 2013 and 2015.  Amgen’s ’878 patent is directed to purifying proteins expressed in non-mammalian systems in both non-native soluble and non-native insoluble forms, including direct capture of such proteins from a refold mixture or a cell lysate pool by a separation matrix.

Sandoz submitted an abbreviated Biologics License Application (“aBLA”) to the Food and Drug Administration (“FDA”) in 2014 in order to market its filgrastim biosimilar, which it later launched after receiving approval in 2015.  Sandoz also submitted an aBLA to market its pegfilgrastim biosimilar in 2016, which has not yet been approved.  Subsequently, Amgen filed an amended infringement complaint in connection with the Sandoz’s filgrastim biosimilar product and later filed an infringement complaint in connection with Sandoz’s pegfilgrastim application, asserting its ’878 and ’427 patents.

In its complaint, Amgen asserted, inter alia, that the process used by Sandoz to manufacture its biosimilar products infringes claim 7 of the ’878 patent.  The purification process used by Sandoz involves a single anion exchange chromatography step with one solution that comprises continuously flowing a refold solution containing filgrastim, a detergent, and other selected components, through a separation matrix.

Claim 7 of Amgen’s ’878 patent recites, in pertinent part:

A method of purifying a protein expressed in a non-native limited solubility form in a non-mammalian expression system comprising…

(e) directly applying the refold solution to a separation matrix under conditions suitable for the protein to associate with the matrix;

(f) washing the separation matrix; and

(g) eluting the protein from the separation matrix, wherein the separation matrix is a non-affinity resin selected from the group consisting of ion exchange, mixed mode, and a hydrophobic interaction resin.

The ’878 patent describes standard capture media used in (e)-(g), providing that the “separation matrix” can be affinity resin, such as an affinity resin selected from the group consisting of Protein A, Protein G and a synthetic mimetic affinity resin, or it can be a non-affinity resin, such as a non-affinity resin selected from the group consisting of ion exchange, mixed mode, and a hydrophobic interaction resin[2].

After applying the refold solution to the separation matrix, the method further comprises (f) “washing the separation matrix” with “any composition, as long as the composition and pH of the wash buffer is compatible with both the protein and the matrix” and (g) “eluting the protein from the separation matrix” using “a solution that interferes with the binding of the adsorbent component of the separation matrix to the protein.”[3]

The district court construed the elements (e)-(g) of claim 7 as three separate steps, including:

(e) applying the refold solution to a column that contains the separation matrix…,

(f) adding a solution into the column…to remove materials in the refold solution that do not interact with the separation matrix…; and

(g) adding a solution into the column…which [h]as the effect of reversing the interactions between the protein and the separation matrix….

(Emphasis added)[4].  As a result, the lower court granted summary judgment that Sandoz’s single step purification process for its filgrastim and pegfilgrastim biosimilars does not infringe claim 7 of the ’878 patent.

Appealing to the Federal Circuit, Amgen argued that the claims of the ’878 patent cover any number of solutions or steps[5]. Amgen asserted that the claim only specifies that the washing and eluting steps are performed in sequence[6].  Amgen argued that, as a result, Sandoz’s purification process infringes claim 7 of the ’878 patent because the refolding solution flowing through the separation matrix would be washed and eluted at any point along the matrix[7].

In response, the Federal Circuit found that the claims when read in light of the specification clearly define the washing and separating procedures as separate functional steps[8].  As a result, the Court found that Sandoz’s purification process employing a single step and solution does not literally infringe claim 7 of the ’878 patent[9].

Amgen also argued that Sandoz’s purification process infringes under the doctrine of equivalents because it “achieves the same functions (washing and eluting), in substantially the same way (binding protein preferentially compared to contaminants, and then raising salt concentration to reverse protein binding) to achieve the same result (protein purification).”[10]

The Federal Circuit responded that Amgen argued beyond the scope of the claims in the ’878 patent.  The Court held that Sandoz’s single step purification process does not function in substantially the same way as the claimed three step process[11]. In this regard, the Court asserted that “[t]he doctrine of equivalents applies only in exceptional cases and is not ‘simply the second prong of every infringement charge, regularly available to extend protection beyond the scope of the claims.’”[12]  Thus, the Court declined to extend the scope of the claims reciting “refolding, “washing,” and “eluting” to cover “nearly any type of adsorbent chromatographic separation” under a doctrine of equivalence, thereby effectively reading out the additional steps required by the claim[13].   

Amgen also appealed a decision by the lower court that Sandoz did not infringe claim 1 of the ’427 patent.  The ’427 patent involves administering G-CSF before providing chemotherapy to a patient.  In pertinent part, claim 1 of the requires “administering to the patient a hematopoietic stem cell mobilizing-effective amount of G-CSF” and “thereafter administering to the patient a disease treating-effective amount of at least one chemotherapeutic agent.”

The lower court construed a “disease treating-effective amount of at least one chemotherapeutic agent” as “an amount sufficient to treat a disease for which at least one chemotherapeutic agent is prescribed.”[14]

Amgen argued that the “disease treating-effective amount” includes administering a chemotherapeutic for the purpose of mobilizing stem cells[15].

The Federal Circuit disagreed, finding that “disease treating-effective amount” requires an amount of chemotherapeutic sufficient to treat the underlying disease[16].

The Court explained that Amgen cannot read the claims differently than they are drafted, specifically, “[h]ad Amgen simply wanted to claim a method of mobilizing stem cells, in any context, it could have done so.”[17]

While the Court’s ultimate conclusion regarding the claim language at issue may not be surprising, after the Court’s ruling in this case, patentees may find enforcing a broader scope of their patent claims more difficult going forward.  As a result, practitioners may need to keep the court’s narrowed view of the doctrine of equivalents in mind for all areas of claim construction practice.

Both inventors and practitioners may also need to be mindful of this case when drafting claims and prosecuting application before the USPTO.  The Court’s decision highlights a heightened need for express language capturing the desired subject matter to be claimed, as it may be more difficult to assert claims under the doctrine of equivalents.

[1] Amgen, Inc. v. Sandoz Int’l GmbH, Appeal No. 2018-1551, slip op. (Fed. Cir. May 8, 2019)

[2] ’878 patent at col. 2, lines 7-12.

[3] ’878 patent at col. 15 line 47 – col. 16, line 9.

[4] Amgen, slip op. at 8

[5] Amgen, slip op. at 8.

[6] Id.

[7] Id.

[8] Id.  (citing Mformation Techs., Inc. v. Research in Motion Ltd., 764 F.3d 1392(Fed. Cir. 2014)); see e.g., (“a claim “requires an ordering of steps when the claim language, as a matter of logic or grammar, requires that the steps be performed in the order written, or the specification directly or implicitly requires”) (citingTop of Form TALtech Ltd. v. Esquel Apparel, Inc., 279 F. App’x 974, 978 (Fed. Cir. 2008)).

[9] Amgen, slip op. at 9.

[10] Id. at 10 (citing Appellant Br. 52).

[11] Id. at 11.

[12] Id. (quoting London v. Carson Pi-rie Scott & Co., 946 F.2d 1534, 1538 (Fed. Cir. 1991)).

[13] Id.at 11.

[14] Id. at 6.

[15] Id. at 14.

[16] Id. at 15.

[17] Id.

On May 20, 2019, the PTAB denied a request for rehearing in Apotex Inc. v. Amgen Inc., Case IPR2016-01542 (Paper 67), but modified its Final Written Decision. In the Final Written Decision, the PTAB found claims 1-17 and 19-24 of U.S. Patent No. 8,952,138 (“the ’138 patent”) unpatentable. The ’138 patent is directed towards a method of refolding a protein expressed in a non-mammalian expression system. Only claim 18 was found patentable, which depends from claim 1 and recites that “the incubation is performed under non-aerobic conditions.”

In its request for rehearing, Apotex asserted that the grounds for rehearing were the PTAB’s interpretation of the claim term “non-aerobic conditions” and the PTAB incorrectly concluded that Apotex failed to demonstrate that claim 18 was unpatentable. The PTAB ordered additional briefing including an opposition to the request for rehearing and briefs from both parties regarding the meaning of the claim term “non-aerobic conditions.”

Apotex argued that the PTAB adopted an erroneous construction of the term “non-aerobic conditions” and that the specification provides a special definition for the term. The specification provides that the term means “any reaction or incubation condition that is performed without intentional aeration of the mixture by mechanical or chemical means.” Paper 67 at 3. The PTAB agreed that it overlooked the special definition in the specification but concluded that the Apotex did not include a proposed construction for “non-aerobic conditions” in its Petition. Apotex argued that its Petition addressed the construction through its statement that “the challenged claims must be given their broadest reasonable interpretations in light of the specification of the ’138 patent. To be clear, any claim terms not included in the following discussion should be given their broadest reasonable construction in light of the specification.” Paper 67 at 4-5. The PTAB disagreed, concluding that the statement does not specifically point it to the special definition of the claim term and instead treats the term as having its plain and ordinary meaning.  The PTAB argued that “non-aerobic” means “the absence of oxygen” when not given a special meaning.

The PTAB then examined various portions of the Petition and expert declaration cited by the Apotex as providing support for its argument that it addressed the issue of the special construction of “non-aerobic conditions.” However, the PTAB was not persuaded. The PTAB argued that there is nothing in the expert declaration suggesting that a special definition for “non-aerobic conditions” existed. The PTAB argued that Apotex’s statement in the Petition that it would have been obvious to “eliminate oxygen from the refolding reaction” was the clearest statement indicating that Apotex meant for “non-aerobic conditions” to mean the elimination of or absence of oxygen. However, it was not enough.  Amgen argued in its Opposition that Apotex’s Request for Rehearing was based on arguments not present its Petition or Reply and the PTAB agreed. Because Apotex failed to demonstrate where the claim construction issue was presented to the PTAB, the PTAB denied the request for rehearing.

However, the PTAB still decided to address the issue of claim construction of “non-aerobic conditions” in view of the additional briefing. The PTAB stated that it requested additional briefing “because the term is expressly defined and we wish to ensure the decision is legally accurate and each party has had adequate opportunity to provide input on the broadest reasonable interpretation of the term.” Paper 67 at 11.

Both parties agreed that the meaning of “non-aerobic conditions” is the express definition provided in the specification. In view of the agreed upon definition, the PTAB then decided to modify its Final Written Decision as it pertains to claim 18. Generally, courts have held that administrative agencies “possess inherent authority to reconsider their decisions, subject to certain limitations, regardless of whether they possess explicit statutory authority to do so.”  Paper 67 at 11 (citing Tokyo Kikai Seisakusho, Ltd. v. United States, 529 F.3d 1352, 1360-61 (Fed. Cir. 2008)). Using the special definition of “non-aerobic conditions”, the PTAB concluded that claim 18 only requires that a reaction be performed without the intentional aeration of the mixture by chemical or mechanical means and because the two prior art references cited by Apotex do not describe intentional aeration, they meet the requirement of claim 18. The PTAB concluded that Apotex demonstrated claim 18 is unpatentable as obvious in view of the prior art and modified its previous decision to reflect this conclusion.

On April 25, 2019, the U.S. Food and Drug Administration (“FDA”) approved new biosimilar product EticovoTM (etanercept-ykro) by Samsung Bioepis.  Eticovo is a biosimilar to Enbrel® (etanercept), which is marketed by Amgen, Inc. (“Amgen”).  Like Enbrel, Eticovo was approved across five eligible indications for the treatment of rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, and polyarticular juvenile idiopathic arthritis.[1]  Eticovo is the 19th FDA-approved biosimilar and the 2nd FDA-approved biosimilar to Enbrel.  Sandoz’s ErelziTM (etanercept-szzs) was approved by the FDA as a biosimilar to Enbrel on August 30, 2016,[2] but Erelzi has yet to launch in the United States due to pending patent litigation.[3]  Sales of Enbrel in the United States last year amounted to $4.807 billion for Amgen.[4]

Samsung Bioepis describes itself as a “biopharmaceutical company dedicated to unlocking the potential of biosimilar medicines.”[5]  According to Samsung Bioepis, its etanercept biosimilar has been approved outside the United States for marketing in 38 countries, including EU member states (January 2016), Canada (August 2016), Brazil (December 2017), Australia (July 2016), and Korea (September 2015),[6] under names such as Benepali and Brenzys.  In the United States, Eticovo is Samsung Bioepis’ second FDA-approved anti-TNF biosimilar, along with Renflexis (infliximab-abda).[7]

On April 30, 2019, directly after the FDA approved Eticovo, a lawsuit was filed in the District of New Jersey against Samsung Bioepis by Immunex Corp. (“Immunex”), Amgen Manufacturing, Ltd. (“AML”), and Hoffmann-La Roche Inc. (“Roche”) (collectively, “the Plaintiffs”).[8]  Immunex and AML are wholly-owned subsidiaries of Amgen.  The case involves five asserted patents that the Plaintiffs allege cover etanercept, methods and materials for manufacture of etanercept, and therapeutic uses of etanercept.  The asserted patents are (i) U.S. Patent Nos. 8,063,182 and 8,163,522, owned by Roche and exclusively licensed to Immunex; and (ii) U.S. Patent Nos. 7,915,225, 8,119,605, and 8,722,631, owned by Immunex.  For each of the asserted patents, Immunex has granted AML an exclusive license or exclusive sublicense.  To note, these are the same plaintiffs and same five patents at issue in the litigation referenced above involving Sandoz and its etanercept biosimilar, Erelzi.

The Biologics Price Competition and Innovation Act (“BPCIA”) provides a framework for patent disputes between biosimilar applicants and reference product sponsors, commonly referred to as the “patent dance.”  According to the Plaintiffs’ complaint, Samsung Bioepis failed to participate in the patent dance because it did not tender the information specified in 42 U.S.C. § 262(l)(2), including a copy of its abbreviated biologics license application (“aBLA”) for Eticovo.  Under the Supreme Court’s decision in Sandoz Inc. v. Amgen, Inc., 137 S. Ct. 1664 (2017), Samsung Bioepis is entitled to decline participation in the patent dance.  However, upon such a failure by the biosimilar applicant to provide the aBLA and information under 42 U.S.C. § 262(l)(2) to the reference product sponsor, the filing of the aBLA can constitute an artificial act of infringement under 35 U.S.C. § 271(e)(2)(C)(ii) and the reference product sponsor is entitled under 42 U.S.C. § 262(l)(9)(C) to bring an action “for a declaration of infringement, validity, or enforceability of any patent that claims the biological product or a use of the biological product.”  Accordingly, the Plaintiffs seek a declaratory judgment that Samsung Bioepis infringed the asserted patents under 35 U.S.C. § 271(e)(2)(C)(ii) by submitting its aBLA for the alleged purpose of obtaining FDA approval to engage in the commercial manufacture, use, or sale of Eticovo prior to the expiration of the patents.  The Plaintiffs also seek a declaratory judgment that Samsung Bioepis has infringed or will fringe the asserted patents under 35 U.S.C. § 271(a), (b), and/or (g).

The complaint also alleges that Samsung Bioepis has not yet provided a notice of commercial marketing pursuant to 42 U.S.C. § 262(l)(8)(A).  That section of the BPCIA states that a biosimilar applicant “shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product.”  Unlike the voluntariness of participation in the patent dance of the BPCIA, the Plaintiffs assert that this notice of commercial marketing is a mandatory requirement that “operates to bar [Samsung] Bioepis from commercial marketing pending, at a minimum, such notice, followed by 180 days.”  The complaint thus seeks a preliminary injunction prohibiting Samsung Bioepis from commercial marketing consistent with the notice period provided by the statute.  The complaint also seeks a preliminary injunction to enjoin Samsung Bioepis from commercial marketing of Eticovo pending a final determination as to infringement, validity, and enforceability of the patents and further seeks a temporary restraining order pending the court’s decision on a preliminary injunction.

We will continue to keep you updated on further developments.

[1] https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/761066Orig1s000ltr.pdf; https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761066s000lbl.pdf

[2] https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/761042Orig1s000ltr.pdf

[3] See Immunex Corp. v. Sandoz Inc., 2:16-cv-01118 (D.N.J.)

[4] https://www.amgen.com/media/news-releases/2019/01/amgen-reports-fourth-quarter-and-full-year-2018-financial-results/

[5] https://www.samsungbioepis.com/en/about/about01.do

[6] https://www.samsungbioepis.com/en/newsroom/newsroomView.do?idx=49&currentPage=1; https://www.samsungbioepis.com/en/product/product01.do

[7] https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761054Orig1s000lbledt.pdf

[8] Immunex Corp. v. Samsung Bioepis Co., Ltd., 2:19-cv-11755 (D.N.J.)

Recently, in Adello Biologics LLC v. Amgen Inc., Case PGR2019-00001 (Paper No. 13) (PTAB Apr. 19, 2019), the PTAB instituted post-grant review of claims 1-30 of U.S. Patent No. 9,856,287 (“the ’287 patent”).  The ’287 patent is the patent at issue in a pending litigation between Amgen and Apotex under the Biologics Price Competition and Innovation Act (BPCIA) in the District Court for the Southern District of Florida.  The ’287 patent, entitled “Refolding Proteins Using a Chemically Controlled Redox State,” contains claims drawn towards methods of refolding proteins expressed in non-mammalian expression systems.  Independent claims 1 and 16 require that the method include “incubating the solution so that at least about 25% of the proteins are properly refolded.”  Independent claims 10 and 26 require that “about 30-80% of the proteins are properly folded.”  Adello Biologics LLC, Apotex Inc., and Apotex Corp. (“Petitioners”) asserted eight grounds of unpatentability for lack of written description support, lack of enablement, anticipation, obviousness and indefiniteness.

In its analysis, the PTAB first determined that the ’287 patent is eligible for post-grant review. Pursuant to the AIA, post-grant review provisions only apply to patents that contain a claim with an effective filing date on or after March 16, 2013. The ’287 patent was filed on Feb. 1, 2017 but claims priority to two applications, one filed in 2009 and another filed in 2010.  Petitioners argued that claims 1-9 and 16-25 were not fully disclosed until they were added by amendment to the claims of the ’287 patent after filing and argued that claims 1-30 are not enabled.  Petitioners argued that the language “at least about 25% of the proteins are properly refolded” does not appear anywhere in the specifications or in the priority applications.  Petitioners equated “at least about 25%” with “25%-100%” and argued that the priority applications fail to provide any disclosure for any percentages of properly refolded proteins over 80%.  Amgen Inc. (“Patent Owner”) argued that the law for written description does not require explicit examples in the specification that cover the entire range of the results disclosed in the claim. The PTAB agreed but noted that “when there is substantial variation with the genus, however, a sufficient variety of species must be described to reflect the variation within the genus.” See Paper 13 at 17. The PTAB then held that the percentages of properly refolded proteins disclosed in the examples of the priority application did not constitute a representative number of species within the genus of “at least about 25%.” The PTAB held that the ’287 patent was eligible for post-grant review and that it is more likely than not that there is inadequate written description support for “at least about 25%” as recited in the claims.

Petitioners further argued that the claims fail to comply with the enablement requirement of 35 U.S.C. § 112(a). For example, Petitioners argued that the claims “recite that the thiol-pair ratio is in the range of 0.0001-100 and do not place a numerical limit on the thiol-pair buffer strength, resulting in a vast number of possible redox conditions” and that the claims do not place a limit on the proteins to be refolded. See Paper 13 at 19. Petitioner argued that due to large number of proteins covered by the claims, the specification fails to provide sufficient guidance to allow a person of ordinary skill in the art to arrive at the claimed ranges of “at least about 25%” or “about 30-80%” of the proteins being properly refolded with undue experimentation.  Patent Owner argued that the Petitioners failed to demonstrate why the experimentation needed would be undue, pointing out that the ’287 patent discloses that optimization of the redox component thiol-pair ratios and thiol-pair buffer strength can be done for each protein. The PTAB rejected these arguments. Instead, the PTAB relied on the unrebutted testimony of Petitioners’ expert who concluded that from the specification, a person of ordinary skill in the art would understand that there is no direct correlation between the thiol-pair ratio and the thiol-pair buffer strength that can be used for all proteins and as a result there is a large number of redox conditions that can tested. The PTAB agreed with the expert that the specification fails to narrow the range of these possible conditions. Thus, the PTAB concluded that it is more likely than not that claims 1-30 are unpatentable for lack of enablement.  Furthermore, in view of the Supreme Court’s recent decision in SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348 (2018), because the PTAB concluded that Petitioners demonstrated more likely than not that claims 1-30 lack enablement and that claims 1-9 and 16-25 failed to provide sufficient written description support, it instituted a post-grant review of all grounds asserted in the Petition.[1]

According to the scheduling order entered with the institution decision, the Patent Owner will have until July 11, 2019 to file a response to the Petition. Subsequently, the Petitioners will have until Oct. 3, 2019 to file a reply to Patent Owner’s response.

[1] The PTAB instituted a post-grant review after its analysis of the written description and enablement grounds. However, the PTAB also made observations in its decision relating to the other asserted grounds as well.

  • FDA approves the second Enbrel® (etanercept) biosimilar—no etanercept biosimilar has launched in the United States to date.
  • FDA approves the fourth Herceptin® (trastuzumab) biosimilar—no trastuzumab biosimilar has launched in the United States to date.
  • European Medicines Agency approves ninth and tenth adalimumab biosimilars and second bevacizumab 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 ten branded biologic drugs totaled approximately $71 billion in 2017[1].  In July 2018, Health and Human Services Secretary Alex Azar announced a Biosimilars Action Plan to aid the development of a market for biosimilars in order to increase competition for biologic drugs, which make up 40% of U.S. pharmaceutical spending.  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 59 applications have been approved in Europe.  Six of the authorizations have been withdrawn post-approval (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, 18 other biosimilar drugs have gained U.S. approval to date (Table 2).

As illustrated in the following graph, while the EU’s significant head start led to an imbalance in the number of biosimilar drugs available in the respective markets, the EU’s relatively higher rate of approvals in recent years has widened its lead over the United States.

Currently, six biosimilar applications are under review by the EMA for marketing authorization (Table 3).  As an increasing number of patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing.  Biosimilars for at least 23 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).

On April 29, 2019, Samsung Bioepis announced the approval of its etanercept biosimilar EticovoTM.  “The approval of ETICOVO adds to our growing portfolio of anti-TNF medicines in the US, where we believe biosimilars can bring meaningful value to the country’s healthcare system,” said Christopher Hansung Ko, President & CEO of Samsung Bioepis. “Through relentless process innovation and an uncompromising commitment to quality, we remain dedicated to advancing one of the industry’s strongest biosimilar pipelines.”  In addition to the United States, Samsung Bioepis’ etanercept biosimilar has been approved for marketing in 38 countries, namely 28 European Union (EU) member states, the European Economic Area (EEA) member states of Norway, Iceland and Liechtenstein, as well as Switzerland, Canada, Brazil, Australia, New Zealand, Israel, and Korea.

In April 2019, the EMA approved two more adalimumab biosimilars to Abbvie’s Humira® in Europe, bringing the total number of approved adalimumab biosimilars to ten.  In February 2019, the EMA approved Pfizer’s Zirabev, which is the second bevacizumab biosimilar to Genentech and Roche’s Avastin® approved in Europe.

The FDA has recently provided useful guidance as reported here.  Under the leadership of Dr. Scott Gottlieb, the FDA advanced new policies aimed at promoting more competition when it comes to biosimilar products as outlined in Dr. Gottlieb’s December 11, 2018 statement on new actions advancing the agency’s biosimilars policy framework.  However, with Dr. Gottlieb’s unexpected resignation on March 5, 2019, it will be up to the next permanent successor to guide stakeholders in navigating the FDA approval process.

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated May 6, 2019).


Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs.

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines compiled on April 8, 2019 and published on April 15, 2019).

Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. and biologics that have biosimilars in the regulatory pipeline.

[1] Based on sales reported by respective manufacturers (1. Humira—Abbvie, 2. Rituxan—Roche, 3. Enbrel—Pfizer/Amgen, 4. Herceptin—Roche, 5. Avastin—Roche, 6. Remicade—Johnson & Johnson/Merck, 7. Lantus—Sanofi, 8. Neulasta—Amgen, 9. Avonex—Biogen, 10. Lucentis—Roche/Novartis).

Many factors contribute to the price that consumers pay for prescription drugs and biologics.  These factors include research and development costs, manufacturing costs, terms negotiated by insurance plans, supply and demand, and intellectual property rights.  Intellectual property rights are often viewed as one of the most significant factors driving high drug and biologic prices. In March, a bipartisan group of six senators sponsored the Biologic Patent Transparency Act (BPTA). The BPTA is intended to “help increase patent transparency, promote biosimilar competition, bring needed biosimilar treatments to patients faster, and ultimately, lower drug prices for consumers.” The bill is intended to impose “transparency requirements that are similar to what are required for small molecule drugs under the Hatch-Waxman framework, which has proven successful in promoting the development and use of generic drugs.”

One target of the bill is “patent thickets.”  Patent thickets are described as ranging from dozens to hundreds of patents intended to block competition, and may include invalid or unenforceable patents.  AbbVie’s Humira has been criticized as a patent thicket with about 136 patents. Though the patent on Humira’s main ingredient expired in 2016, some patents directed to processes and techniques required to replicate Humira remain in force until 2034. Biosimilar competition would be blocked until 2023 when settlements will enable several companies to market biosimilars while paying AbbVie a royalty.  Since biologics are typically produced in living cells, the process often requires complex steps with more possible variations which can be patented. Johnson & Johnson’s Remicade is another biologic with more than 100 patents. The BPTA would require companies to disclose all patents that protect their biologics, which could make it easier for competitors to evaluate and develop generic versions. If a patent is not included in the list in a timely manner, no action for infringement of that patent could be brought.

The bill would also make FDA’s Purple Book a publicly available, single, searchable list which would include information on:

  • Patents that claim and relate to FDA-approved biological products, for which a claim of patent infringement could reasonably be asserted by the holder, including manufacturing processes;
  • Official and proprietary name of each biological product;
  • The date of licensure and application number for each product;
  • Information related to determinations of biosimilarity and interchangeability;
  • Information related to marketing status, dosage form, route of administration, reference product, and any periods of exclusivity related to the product and the date that the exclusivity expires; and
  • Approved indications.

Another goal of the bill is to limit patent enforceability of later filed patents by the biologic manufacturer when a biosimilar application has already been filed with the FDA by barring some claims of infringement for patent owners that do not timely disclose their patents. In other words, the bill is intended to discourage patent owners from filing numerous patent applications covering minor variations of the product, processes for making the product, or methods of using the product, long after the patent on the original product has issued. However, the language of the bill does not specifically reference the date that a biosimilar application has been filed.  The language in the bill regarding the restriction on claims of patent infringement only states that patents which are not timely included on the list cannot be used to bring an action for infringement. There is no specific language in the bill which would limit the enforceability of later filed patents by the biologic manufacturer when a biosimilar application has already been filed with the FDA, as long as such patents are disclosed in a timely manner.   Since the language “timely included in such list” is not limited to inclusion on the list before a biosimilar application is filed, an argument could be made that a patent which issues after a biosimilar application has been filed can still be timely disclosed.

Recently, there have been a number of legislative proposals with a goal of reducing drug and biologic product prices. While patents are the focus of the BPTA, other proposals include closing a loophole in the Food and Drug Administration’s Risk Evaluation and Mitigation Strategies (REMS) program which denied generic drug and biosimilar manufacturers access to product samples; prohibiting anticompetitive agreements between drug/biologic and generic/biosimilar manufacturers; allowing Medicare to negotiate prices with pharmaceutical companies; limiting regulatory exclusivities based on price increases; and restricting the price of prescription drugs/biologics in the U.S. based on the median price in Canada, the United Kingdom, France, Germany and Japan.  It is clear that rising drug prices are a concern, however, any public policy on drug pricing must find a balance between providing incentives to manufacturers for developing new medicines and providing affordable drug/biologic prices to consumers.