Ex Parte Salfeld et alDownload PDFPatent Trial and Appeal BoardMay 15, 201713736931 (P.T.A.B. May. 15, 2017) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 13/736,931 01/08/2013 Jochen G. SALFELD 3685.001000C/EKS/KRM 6933 135005 7590 05/16/2017 STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C. 1100 NEW YORK AVENUE, N.W. WASHINGTON, DC 20005 EXAMINER ROMEO, DAVID S ART UNIT PAPER NUMBER 1647 MAIL DATE DELIVERY MODE 05/16/2017 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) FF1. UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte JOCHEN G. SALFELD, DEBORAH J. ALLEN, ZEHRA KAYMAKCALAN, BORIS LABKOVSKY, JOHN A. MANKOVICH, BRIAN T. MCGUINNESS, ANDREW J. ROBERTS, PAUL SAKORAFAS, HENDRICUS R.J.M. HOOGENBOOM, DAVID SCHOENHAUT, TRISTAN J. VAUGHAN, MICHAEL WHITE, and ALISON J. WILTON1 ____________ Appeal 2015-007511 Application 13/736,931 Technology Center 1600 ____________ Before FRANCISCO C. PRATS, JEFFREY N. FREDMAN, and RYAN H. FLAX, Administrative Patent Judges. FLAX, Administrative Patent Judge. DECISION ON APPEAL This is a decision on appeal under 35 U.S.C. § 134(a) involving claims directed to a liquid pharmaceutical composition for the treatment of a disorder in which TNFα is detrimental. Claim 20 is on appeal as rejected under the doctrine of non-statutory obviousness type double patenting. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellants identify the Real Party in Interest as AbbVie Biotechnology Ltd. App. Br. 3. Appeal 2015-007511 Application 13/736,931 2 STATEMENT OF THE CASE Antibodies are proteins (also called immunoglobulins) normally produced by certain white blood cells (plasma cells) in response to entry into the body of a foreign substance (antigen) in order to render it harmless.2 The Specification states, “[t]umor necrosis factor α (TNFα) is a cytokine produced by numerous cell types, including monocytes and macrophages, that was originally identified based on its capacity to induce the necrosis of certain mouse tumors.” Spec. 1:20–22. Further, [b]ecause of the harmful role of human TNFα (hTNFα) in a variety of human disorders, therapeutic strategies have been designed to inhibit or counteract hTNFα activity. In particular, antibodies that bind to, and neutralize, hTNFα have been sought as a means to inhibit hTNFα activity. Some of the earliest of such antibodies were mouse monoclonal antibodies (mAbs), secreted by hybridomas prepared from lymphocytes of mice immunized with hTNFα. Id. at 1:33–2:2. “Th[e] invention provides human antibodies, preferably recombinant human antibodies, that specifically bind to human TNFα.” Id. at 3:25–26. Appellants explain, Claim 20 relates to a liquid pharmaceutical composition for the treatment of a disorder in which TNFα is detrimental, comprising a recombinant anti-TNFα antibody produced by Chinese hamster ovary (CHO) cells and a pharmaceutically acceptable carrier. The claimed antibody has light and heavy variable regions corresponding to adalimumab (sold under the 2 Oxford Dictionary of Biology 7th ed., antibody (2015), available at http://www.oxfordreference.com/view/10.1093/acref/9780198714378.001.0 001/acref-9780198714378-e-262?rskey=hYIlYh&result=301 (visited May 10, 2017). Appeal 2015-007511 Application 13/736,931 3 trade name HUMIRA®), which was the first fully human monoclonal antibody approved by the United States Food and Drug Administration (FDA). App. Br. 10 (internal footnotes omitted). Appellants further explain, HUMIRA® is approved for use in the treatment of multiple diseases, including moderate to severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, moderate to severe Crohn’s disease, moderate to severe polyarticular juvenile idiopathic arthritis, and moderate to severe plaque psoriasis, and has proven to be highly effective and safe as a therapeutic antibody due, at least in part, to its minimal levels of immunogenicity in human patients. Id. at 11 (internal footnote omitted). The appealed claim can be found in the Claims Appendix of the Appeal Brief; it reads as follows: 20. A liquid pharmaceutical composition for the treatment of a disorder in which TNFα is detrimental, comprising a recombinant anti-TNFα antibody produced by Chinese hamster ovary (CHO) cells and a pharmaceutically acceptable carrier, wherein the antibody comprises a human kappa light chain constant region and a human IgG1 heavy chain constant region, wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO:1, and the heavy chain variable domain of the antibody comprises the amino acid sequence SEQ ID NO:2, and wherein the liquid composition is suitable for subcutaneous injection in a human subject. App. Br. 65 (Claims App’x). Appeal 2015-007511 Application 13/736,931 4 The following rejections are on appeal:3 A. Claim 20 stands rejected on the ground of nonstatutory obviousness-type double patenting over claims 1–5 and 7 of Salfeld 8134 in view of Ramage,5 Goochee,6 and Trill.7 Ans. 4. B. Claim 20 stands rejected on the ground of nonstatutory obviousness-type double patenting over claims 18–41 and 54–56 of Salfeld 8948 in view of Le,9 Ramage, Goochee, and Trill. Ans. 54–55. C. Claim 20 stands rejected on the ground of nonstatutory obviousness-type double patenting over claims 1–6 of Salfeld 40110 in view of Ramage, Goochee, and Trill. Ans. 60. D. Claim 20 stands rejected on the ground of nonstatutory obviousness-type double patenting over claims 1–15, 27–40, 52–60, 72–79, 3 Claim 20 was also rejected over U.S. Patent Application No. 14/183,845, which was abandoned January 6, 2016. The respective rejection is dismissed as moot. 4 U.S. Patent No. US 8,197,813 B2 (issued June 12, 2012 to Jochen G. Salfeld et al.) (“Salfeld 813”). 5 U.S. Patent No. 5,644,036 (issued July 1, 1997 to Paul Ian Nicholas Ramage and Geoffrey Allen) (“Ramage”). 6 Charles F. Goochee et al., The Oligosaccharides of Glycoproteins: Bioprocess Factors Affecting Oligosaccharide Structure and their Effect On Glycoprotein Properties, 9 BIOTECH 1347–55 (1991) (“Goochee”). 7 John J. Trill et al., Production of Monoclonal Antibodies in COS and CHO Cells, 6 CURRENT OP. IN BIOTECH 553–60 (1995) (“Trill”). 8 U.S. Patent No. US 8,414,894 B2 (issued Apr. 9, 2013 to Jochen G. Salfeld et al.) (“Salfeld 894”). 9 U.S. Patent No. 5,656,272 (issued Aug. 12, 1997 to Junming Le et al.) (“Le”). 10 U.S. Patent No. US 8,372,401 B2 (issued Feb. 12, 2013 to Jochen G. Salfeld et al.) (“Salfeld 401”). Appeal 2015-007511 Application 13/736,931 5 91–99, 111–118, 130–132 of Salfeld 76111 in view of Gombotz,12 Ramage, Goochee, and Trill. Ans. 65. E. Claim 20 stands rejected on the ground of nonstatutory obviousness-type double patenting over claims 1–30 of Salfeld 38213 in view of Ramage, Goochee, and Trill. Ans. 70. FINDINGS OF FACT Unless otherwise indicated herein, we adopt the Examiner’s findings of fact, reasoning on scope and content of the prior art, and conclusions set out in the Final Action and Answer regarding the rejection. We set forth the following findings of fact to highlight certain evidence. FF2. Salfeld 813 claims 1, 4, 5, and 7 recite: 1. An isolated human antibody, or an antigen-binding portion thereof, that dissociates from human TNFα (hTNFα) with a Kd of 1 x 10-8 M or less and a Koff rate constant of 1 x 10-3 s-1 or less, both determined by surface plasmon resonance, and inhibits human TNFα-induced expression of ELAM-1 on human umbilical vein endothelial cells. 4. The isolated human antibody, or antigen-binding portion thereof, of claim 1, which is a recombinant antibody, or antigen- binding portion thereof. 5. The isolated human antibody of claim 1, which has an IgG1 heavy chain constant region. 11 U.S. Patent No. US 7,588,761 B2 (issued Sept. 15, 2009 to Jochen G. Salfeld et al.) (“Salfeld 761”). 12 U.S. Patent No. 6,036,978 (issued Mar. 14, 2000 to Wayne R. Gombotz and SiowFong Wee) (“Gombotz”). 13 U.S. Patent No. 6,090,382 (issued July 18, 2000 to Jochen G. Salfeld et al.) (“Salfeld 382”). Appeal 2015-007511 Application 13/736,931 6 7. A pharmaceutical composition comprising the isolated human antibody of claim 1, and a pharmaceutically acceptable carrier. Salfeld 813 51:2–52:10; see also Final Action 4–7, 19–20, and Ans. 3, 4–5, 7, 15, 36, 40, 48–49, 52–53 (discussing Salfeld 813). FF3. Salfeld 894 claims 38–40 and 55 recite: 38. The isolated human antibody, or antigen-binding portion thereof, of claim 18 or 25, with a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. 39. The isolated human antibody, or antigen-binding portion thereof, of claim 18 or 25, which has an IgG1 or an IgG4 heavy chain constant region. 40. The isolated human antibody, or antigen-binding portion thereof, of claim 18 or 25, which has a kappa light chain constant region. 55. A pharmaceutical composition comprising an isolated human antibody, or antigen-binding portion thereof, which dissociates from human TNFα with a Kd of 1 x 10-8 M or less and a Koff rate constant of 1 x 10-3 s-1 or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1-10-7 M or less, and a pharmaceutically acceptable carrier, wherein the composition is suitable for administration according to a mode selected from the group consisting of an intravenous injection, a subcutaneous injection, an intraperitoneal injection, and an intramuscular injection. Salfeld 894 53:24–35, 54:53–63; see also Final Action 28–33, and Ans. 3, 54–55, 57–59 (discussing Salfeld 894). Appeal 2015-007511 Application 13/736,931 7 FF4. Salfeld 401 claims 1 and 5 recite: 1. An isolated human anti-TNFα antibody, or an antigen-binding portion thereof, comprising a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2, wherein the antibody, or antigen- binding portion thereof, comprises an IgG1 heavy chain constant region and a kappa light chain constant region. 5. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 1, and a pharmaceutically acceptable carrier. Salfeld 401 49:60–67, 51, 4–6; see also Final Action 33–37, and Ans. 3, 60, 62–64 (discussing Salfeld 401). FF5. Salfeld 761 claims 78–80 recite: 78. A composition comprising an absorption delaying agent and a human antibody that binds TNFα and is the antibody D2E7, or an antigen-binding portion thereof. 79. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 78, and a pharmaceutically acceptable carrier. 80. A method for treating a subject suffering from a disorder in which TNFα activity is detrimental comprising administering to the subject the pharmaceutical composition of claim 79. Salfeld 761 55:14–23; see also Final Action 37–41, and Ans. 3, 65, 67–69 (discussing Salfeld 761). FF6. “Antibody D2E7” is the human anti-TNFα antibody found in Humira®, also called adalimumab. App. Br. 10 n.7. FF7. Salfeld 382 claims 15, 16, and 24 recite: 15. An isolated human antibody, or an antigen binding portion thereof, with a light chain variable region (LCVR) comprising Appeal 2015-007511 Application 13/736,931 8 the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. 16. The isolated human antibody of claim 15, which has an IgGl heavy chain constant region. 24. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of any one of claims 1-23, and a pharmaceutically acceptable carrier. Salfeld 382 56:57–63, 57:28–30; see also Final Action 42–45, and Ans. 3, 70, 72–74 (discussing Salfeld 382). FF8. It is not disputed that the “human antibody,” “human anti- TNFα antibody,” “human antibody that binds TNFα,” “antibody [that] comprises the amino acid sequence of SEQ ID NO: 1, and . . . the amino acid sequence of SEQ ID NO: 2” and “the antibody D2E7,” recited by the various claims of the Salfeld patents identified in the findings of fact, supra, and the “anti-TNFα antibody” and “antibody [that] comprises the amino acid sequence of SEQ ID NO:1, and . . . the amino acid sequence SEQ ID NO:2,” recited by appealed claim 20, are the same. See generally App. Br. and Reply Br. FF9. Ramage “relates to a purified preparation of monoclonal antibodies against the antigen CDw52, to their use in therapy and to processes for their production” (Ramage 1:9–11), in particular, to “an IgG1 antibody, [which] has been humanized[,] . . . known as Campath 1H” (id. 2:1–3) (a lymphoma cancer treatment). See also Final Action 3–7, 12, and 14–17, and Ans. 3–4, 6–7, 9–11, and 14–15 (discussing Ramage). Ramage discloses “the purified anti-CDw52 antibody of the invention may be a . . . human antibody.” Ramage 6:9–10; see also Appeal 2015-007511 Application 13/736,931 9 Final Action 4, 7, 11, 26–29, 33, 37–38, 41, 42, and 45, and Ans. 3, 4– 5, 14–15, 17–18, 24–26, 29–30, 34–36, 38–40, 42–43, 46–48, 54, 55– 56–57, 59, 60–61, 64, 65–66, 69–71, and 74–75 (discussing Ramage). FF10. Ramage discloses that “[a]ntibodies which are intended for use in medical therapy may need to be administered repeatedly, so the need to remove foreign immunoglobulins is important as such administration may produce an immune response and induce nephrotoxicity, serum sickness and in severe cases anaphylactic shock.” Ramage 2:15–20; see also Final Action 4, 7, 11, 26–29, 33, 37–38, 41, 42, and 45, and Ans. 3, 4–5, 14–15, 17–18, 24–26, 29–30, 34–36, 38–40, 42–43, 46–48, 54, 55–56–57, 59, 60–61, 64, 65–66, 69–71, and 74–75 (discussing Ramage). FF11. Ramage discloses “use of a purified preparation of an anti- CDw52 antibody in the manufacture of a medicament . . . [for] treating a human being.” Ramage 6:50–54; see also Final Action 4, 7, 11, 26–29, 33, 37–38, 41, 42, and 45, and Ans. 3, 4–5, 14–15, 17–18, 24–26, 29–30, 34–36, 38–40, 42–43, 46–48, 54, 55–56–57, 59, 60–61, 64, 65–66, 69–71, and 74–75 (discussing Ramage). FF12. Ramage discloses “[s]uch formulations preferably include, in addition to antibody, a physiologically acceptable diluent or carrier . . . . Suitable carriers include but are not limited to physiological saline . . . . Routes of administration are routinely parenteral including intravenous, intramuscular, subcutaneous and intraperitoneal injection or delivery.” Ramage 6:64–7:10; see also Final Action 4, 7, 11, 26–29, 33, 37–38, 41, 42, and 45, and Ans. 3, 4– Appeal 2015-007511 Application 13/736,931 10 5, 14–15, 17–18, 24–26, 29–30, 34–36, 38–40, 42–43, 46–48, 54, 55– 56–57, 59, 60–61, 64, 65–66, 69–71, and 74–75 (discussing Ramage). FF13. Ramage discloses that “[a]ntibodies according to the invention may be prepared using a recombinant expression system, the preferred system is a mammalian expression system using Chinese hamster ovary (CHO) cells.” Ramage 3:52–55; see also Final Action 4, 7, 11, 26–29, 33, 37–38, 41, 42, and 45, and Ans. 3, 4–5, 14–15, 17–18, 24–26, 29–30, 34–36, 38–40, 42–43, 46–48, 54, 55–56–57, 59, 60–61, 64, 65–66, 69–71, and 74–75 (discussing Ramage). FF14. Goochee discloses that workers in the relevant technical field have detected the presence of the Galα(1,3)Gal epitope on the surface of SP/2 myeloma cells and on secreted mouse monoclonal antibodies. . . . In contrast, the Galα(1,3)Gal epitope is not found on the cell surface of many cultured human cells, including normal human fibroblasts and the HL60 and HeLa cell lines. This epitope is also not apparent in glycoproteins from recombinant CHO cells, including human interferon-B1, EPO, and t-PA, nor is if found in EPO produced by recombinant BHK cells. These data suggest that α(1,3)galactosyltransferase activity in these two rodent cell types is diminished or absent. The CHO cell line does harbor DNA that hybridizes with a probe or a murine α(1,3)galactosyltransferase, but northern blot analysis reveals no evidence of α(1,3)galactosyltransferase message in CHO cells. Goochee 1350 (internal citations omitted); see also Final Action 4–5, 15, 17, 18, 21, 24–26, 28, 30, 33–34, 37–38, and 42–43, and Ans. 3–5, 8, 13–18, 22–24, 29, 33, 36, 38–40, 42–43, 45–48, 54–56, 60–61, 65– 66, and 70–71 (discussing Goochee). Appeal 2015-007511 Application 13/736,931 11 FF15. Goochee discloses “approximately 100 µg/ml of human IgG recognize the ‘Galα(1,3)Gal’ structure generated by mammalian cell lines possessing α(1,3)galactosyltransferase.” Goochee 1351 (internal citations omitted); see also Final Action 4–5, 15, 17, 18, 21, 24–26, 28, 30, 33–34, 37–38, and 42–43, and Ans. 3–5, 8, 13–18, 22– 24, 29, 33, 36, 38–40, 42–43, 45–48, 54–56, 60–61, 65–66, and 70–71 (discussing Goochee). FF16. Further to the preceding findings of fact regarding Goochee, Goochee discloses: Human EPO produced by recombinant CHO cells is the only recombinant therapeutic glycoprotein for which extensive clinical trial data involving antibody development has been published. No antibodies against recombinant EPO have been detected in patients receiving this product, even after chronic administration up to 18 months. Takeuchi and coworkers have reported the oligosaccharide structures from human urinary EPO and recombinant CHO-derived EPO to be essentially identical, with the exception that the CHO-produced material contains sialic acid only in an α2,3 linkage, while the human urinary material contains both the α2,3 and α2,6 linkages. The absence of antibodies to EPO from recombinant CHO is an important and encouraging result. Goochee 1351 (internal citations omitted); see also Final Action 4–5, 15, 17, 18, 21, 24–26, 28, 30, 33–34, 37–38, and 42–43, and Ans. 3–5, 8, 13–18, 22–24, 29, 33, 36, 38–40, 42–43, 45–48, 54–56, 60–61, 65– 66, and 70–71 (discussing Goochee). FF17. Further to the preceding findings of fact regarding Goochee, Goochee concludes: “Chinese hamster ovary cells have emerged as the cell line of first choice for the synthesis of Appeal 2015-007511 Application 13/736,931 12 recombinant human therapeutic glycoproteins, although CHO cells do poses deficiencies that may limit their applicability in specific cases . . . .” Goochee 1353; see also Final Action 4–5, 15, 17, 18, 21, 24– 26, 28, 30, 33–34, 37–38, and 42–43, and Ans. 3–5, 8, 13–18, 22–24, 29, 33, 36, 38–40, 42–43, 45–48, 54–56, 60–61, 65–66, and 70–71 (discussing Goochee). FF18. Trill is directed to the production of monoclonal antibodies in COS and CHO cells and discloses “[i]n order to meet the demand for clinical supplies, a gradual increase has occurred in the usage of dihydrofolate reductase negative (DHFR-) Chinese hamster ovary (CHO) cells for large-scale antibody production,” and “[u]sing a variety of mammalian expression vectors and selection/amplification protocols, CHO cell lines capable of producing monoclonal antibodies at levels exceeding 1gl-1 can now be obtained in an almost routine fashion.” Trill 553 (abstract); see also Final Action 4–5, 22–23, 28, 30, 33–34, 37–39, and 42–43, and Ans. 4–6, 14–15, 17–21, 28–29, 36, 40, 43, 46–48, 53–56, 60–61, 65–66, and 70–72 (discussing Trill). FF19. Trill disclosed: In the recent past, myeloma cells (SP 2/0, YB 2/0, NSO and P3X63.Ag8.653) were primarily used for high-level production of mAbs. Over the past few years, however, more and more laboratories have been reporting the successful use of DHFR– CHO cells (DUKX–B11 and DG–44) for high-level mAb production. For example, Page and Sydenham used DUKX–B11 CHO cells to generate a stable cell line expressing the humanized mAb Campath-1H at levels of 100 milligrams per 106 cells per day. Using the same host cells, Fouser et al. reported the generation of cell lines expressing a chimeric anti-ganglioside GD2 antibody at 80–110 milligrams per 106 cells per day. Appeal 2015-007511 Application 13/736,931 13 Recently, Reff et al. have reported the utility of DG44 CHO cells in producing a chimeric antibody against CD20 at levels of 30 milligrams per 106 cells per day after only one round of gene amplification (see below). Trill 555 (internal citations omitted); see also Final Action 4–5, 22– 23, 28, 30, 33–34, 37–39, and 42–43, and Ans. 4–6, 14–15, 17–21, 28–29, 36, 40, 43, 46–48, 53–56, 60–61, 65–66, and 70–72 (discussing Trill). FF20. Further to the preceding findings of fact relating to Trill, Trill identifies the following advantages offered by protein (mAb) production via CHO cells: (1) cells are readily transfectable; (2) able to grow in suspension and serum-free medium; (3) capable of growth at high densities; (4) based on all data, no differences exist in the function of mAbs produced in either myeloma or CHO cells; (5) well established track record for expressing heterologous gene products (other than mAbs); (6) proven successful in the co-expression of foreign genes, such as those encoding glutamine synthetase (GS), adenosine deaminase (ADA), and DHFR; (7) reports describing the modification of CHO cells to express heterologous proteins quickly and at high levels (e.g., stable expression of adenovirus E1A); and (8) high-level expression achieved. Trill 555–56; see also Final Action 4–5, 22–23, 28, 30, 33–34, 37–39, and 42–43, and Ans. 4–6, 14–15, 17–21, 28–29, 36, 40, 43, 46–48, 53–56, 60–61, 65–66, and 70–72 (discussing Trill). FF21. Le is directed to “[a]nti-TNF antibodies, fragments and regions thereof which are specific for human tumor necrosis factor-α Appeal 2015-007511 Application 13/736,931 14 (TNFα) and are useful in vivo for diagnosis and therapy of a number of TNFα-mediated pathologies and conditions . . . .” Le Abstract; see also Final Action 28–29, and Ans. 54–55 and 58–59 (discussing Le). FF22. Le discloses that, in expressing anti-TNF peptides of Ab fragments, [p]referred hosts are bacterial or eukaryotic hosts including bacteria, yeast, insects, fungi, bird and mammalian cells either in vivo, or in situ, or host cells of mammalian, insect, bird or yeast origin. It is preferred that the mammalian cell or tissue is of human, primate, hamster, rabbit, rodent, cow, pig, sheep, horse, goat, dog or cat origin, but any other mammalian cell may be used. Le 26:30–36; see also Final Action 28–29, and Ans. 54–55 and 58–59 (discussing Le). FF23. Further to the immediately preceding finding of fact, Le discloses: Preferred hosts are mammalian cells, grown in vitro or in vivo. Mammalian cells provide post-translational modifications to immunoglobulin protein molecules including leader peptide removal, folding and assembly of H and L chains, glycosylation of the antibody molecules, and secretion of functional antibody protein. Mammalian cells which can be useful as hosts for the production of antibody proteins, in addition to the cells of lymphoid origin described above, include cells of fibroblast origin, such as Vero (ATCC CRL 81) or CHO-K1 (ATCC CRL 61). Le 30:13–23; see also Final Action 28–29, and Ans. 54–55 and 58–59 (discussing Le). Appeal 2015-007511 Application 13/736,931 15 FF24. Le discloses: treatment compris[ing] parenterally administering a single or multiple doses of the antibody, fragment or derivative. Preferred for human pharmaceutical use are high affinity potent hTNFα-inhibiting and/or neutralizing murine and chimeric antibodies, fragments and regions of this invention. . . . [And] [b]ecause proteins are subject to being digested when administered orally, parenteral administration, i.e., intravenous, subcutaneous, intramuscular, would ordinarily be used to optimize absorption. Le 35:10–24; see also Final Action 28–29, and Ans. 54–55 and 58–59 (discussing Le). FF25. Gombotz discloses: This invention pertains to controlled release pharmaceutical compositions containing a polypeptide [including a monoclonal antibody that is immunoreactive against TNFα, IL-6 or IL-1] and a salt of an alginic acid. This invention also is directed to methods of treating inflammatory bowel diseases that are mediated by tumor necrosis factor, interleukin- 6 or interleukin-1 by administering such controlled enteric release formulations to a patient. Gombotz 1:10–16, 2:56–64, 4:16–17; see also Final Action 37 and 41, and Ans. 3, 65, and 70 (discussing Gombotz). FF26. Smith14 discloses that “the α1,3-galactosyltransferase . . . transfers Gal from UDP-Gal in α1,3-linkage” and, unless engineered to do so, CHO cells do not contain murine α1,3-galactosyltransferase genomic DNA sequences and do not exhibit α1,3-galactosyltransferse 14 Smith et al., Transfer and Expression of a Murine UDP-Gal:β-D-Gal- αl,3-Galactosyltransferase Gene in Transfected Chinese Hamster Ovary Cells, 265 J. BIO. CHEM. 6225–34 (1990) (“Smith”). Appeal 2015-007511 Application 13/736,931 16 activity. Smith 6225, 6232; see also Final Action 17, 19, and 25, and Ans. 4, 23, 39, 42, and 45 (discussing Smith). FF27. Appellants state, “Appellants do not dispute that it was known in the prior art that CHO cells did not express α-1,3- galactosyltransferase” (App. Br. 36) and further concede, “[t]he person of ordinary skill may have even been motivated to try CHO cells given the fact that CHO cells lack α-1,3-galactosyltransferase” (Reply Br. 15). FF28. Appellants contend the person of ordinary skill in the art: in February 1996, is a Senior Scientist with experience in the discovery, production and characterization of therapeutic antibodies, including murine, chimeric or humanized monoclonal antibodies. This hypothetical person of ordinary skill in the art also has experience with research-scale manufacturing, ultimately leading to commercial scale manufacturing (given that the antibody is part of a pharmaceutical composition). This ordinarily skilled person is either: (A) a person with at least a Bachelor’s degree in biology, chemistry, biochemistry, chemical engineering, or a related field who has multiple years of experience in antibody production in an industrial setting; or (B) a person with an advanced degree (M.S. or Ph.D.) in biology, chemistry, biochemistry, chemical engineering, or a related field who has at least 2-3 years of experience in antibody production in an industrial setting. Declaration Under 37 C.F.R. § 1.132 of Dr. Peter Mezes (dated Sept. 4, 2014) (“Mezes Decl.”) ¶ 12. The Examiner does not contend otherwise and we accept this as representative of the relevant level of skill in the art. FF29. As of February 9, 1996, there would have been motivation to produce a human anti-TNFα antibody, according to appealed claim Appeal 2015-007511 Application 13/736,931 17 20, using Chinese Hamster Ovary (CHO) cells as host cells, as a liquid pharmaceutical composition having a pharmaceutically acceptable carrier, and suitable for subcutaneous injection in a human subject, and the skilled artisan would have had a reasonable expectation of successfully so doing. See findings of fact, supra. DISCUSSION I. CLAIM INTERPRETATION There is a dispute regarding the interpretation of claim 20, specifically the meaning of the claim language, “pharmaceutical” or “pharmaceutical composition,” which impacts each determination of the Examiner and each argument set forth by Appellants. See Reply Br. 3–5; App. Br. 17, 19–20, 22–26, 28, 31, 45, 48–49, 51, 52, and 54; Ans. 9–10, 15, 17, 19, 21–22, 24– 25, 27–30, and 43–44; and Final Action 24; see also Mezes Decl. ¶¶ 14, 16, 17, 18, 22–24, and 25 (“an industrial setting” and “commercial purposes” established as the perspective from which declarant forms his opinions). Claim 20 does not expressly recite producing antibodies on a commercial or industrial scale or a product suitable for FDA approval or commercialization. Thus, the issue to be resolved is whether the term “pharmaceutical” (or “pharmaceutical composition”) invokes such commercial and/or industrial production and/or regulatory-approval concerns for the skilled artisan. “Absent claim language carrying a narrow meaning, the PTO should only limit the claim based on the specification or prosecution history when those sources expressly disclaim the broader definition.” In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004). The claim language is accorded its plain Appeal 2015-007511 Application 13/736,931 18 meaning under the broadest reasonable interpretation of the claims. Cuozzo Speed Tech., LLC v. Lee, 136 S. Ct. 2131, 2145 (2016) (the Patent Office, for more than 100 years, has applied the broadest reasonable construction standard in proceedings). “The ordinary and customary [plain] meaning of a claim term may be determined by reviewing a variety of sources. Some of these sources include the claims themselves; dictionaries and treatises; and the written description, the drawings, and the prosecution history.” Brookhill-Wilk 1, LLC v. Intuitive Surgical, Inc., 334 F.3d. 1294, 1298 (Fed. Cir. 2003) (citations omitted). Appellants contend the Examiner did not give enough weight to the claim term “pharmaceutical” when construing the claims and that the skilled artisan’s choice of a host cell to produce the recited antibodies must take this into account, i.e., consider commercialization requirements and FDA regulations when analyzing motivation (for obviousness). Reply Br. 4. Appellants contend the claim term “pharmaceutical” limits the invention to a “commercial product (i.e., a pharmaceutical formulation)” and, in turn that “‘liquid pharmaceutical formulation’” means “a commercial product which would be produced on an industrial scale.” Id.; App. Br. 25–26. As support for this position, Appellants cite the Macmillan dictionary and provide the following definition of pharmaceutical: “relating to the production or sale of medicines and drugs used for treating medical conditions.” Id. Appellants also cite this same dictionary for a definition of formulation, as follows: “a product such as a drug or skin cream.” Id. at 26. The Examiner does not expressly interpret the claim term “pharmaceutical,” but responded to Appellants’ arguments by finding that Appeal 2015-007511 Application 13/736,931 19 the claims do not require production on a commercial and/or industrial scale. Nor do the claims require stable antibody production and high yields. . . . . . . [And,] there is no requirement in patent law that a person of ordinary skill be motivated to develop the claimed invention based on a rationale that forms the basis for FDA approval. Ans. 21–22. We look to the Specification to determine whether it assigned a particular meaning to the term “pharmaceutical” (or “pharmaceutical composition”). The Specification uses the term, but does not define it. See Spec. 28:19–26. The Specification indicates that “pharmaceutical compositions [can be] suitable for administration to a subject” and can include “a pharmaceutically acceptable carrier,” which is identified by several examples, which are identified as being “physiologically compatible.” Id. Further, the Specification indicates that “pharmaceutical compositions of the invention may include a ‘therapeutically effective amount’ or a ‘prophylactically effective amount’ of an antibody or antibody portion of the invention.” Spec. 34:3–5. Thus, we find the Specification does not provide a definition for the claim term “pharmaceutical,” and we find the claim should be interpreted per its plain meaning as would be understood by the skilled artisan. We consider Appellants’ evidence regarding their contended meaning of “pharmaceutical,” identified, supra. Appellants unnecessarily introduce into their proposed construction the term formulation, which is not a claim term and is superfluous in view of the claim term composition, and then seek to also construe this newly introduced term in addition to the claim term pharmaceutical. We find this does not foster a better understanding of the Appeal 2015-007511 Application 13/736,931 20 disputed claim language. While the definition cited by Appellants from Macmillan is a valid definition, it relates to the term pharmaceutical’s use as a descriptive term, an adjective used to describe a characteristic of another thing, e.g., a pharmaceutical company describes a company that makes and/or sells pharmaceuticals. Claim 20, however, uses the term pharmaceutical (or pharmaceutical composition) to identify a thing (as a noun, that is, something for the treatment of a disorder in which TNFα is detrimental). Thus, we look for a definition consistent with this usage. We look to the Merriam-Webster dictionary, which defines the term pharmaceutical (noun) as: “a medicinal drug.”15 Nowhere does the Specification use the term pharmaceutical (or pharmaceutical composition) in a way that is inconsistent with this definition or to invoke any commercialization, industrial-scale production, or FDA-approvability considerations. We understand “a medicinal drug” to be the plain meaning of the term pharmaceutical (or pharmaceutical composition) as it would be understood by one of ordinary skill in the art as of the invention date. Had Appellants desired (or if they desire) a more restrictively defined invention that does invoke concepts of commercialization, industrial-scale, and/or FDA-approvability, properly specific and definitive claim language could have been (or could be) used. 15 Merriam-Webster, pharmaceutical, available at https://www.merriam- webster.com/dictionary/pharmaceutical (visited Apr. 27, 2017). (cf. WEBSTER’S II NEW RIVERSIDE UNIVERSITY DICTIONARY 880 (1984) (“Pharmaceutical . . . n. A drug or medication”)). Appeal 2015-007511 Application 13/736,931 21 We address Appellants’ arguments and evidence and the Examiner’s determinations and evidence in view of this interpretation of the disputed claim language. II. OBVIOUSNESS-TYPE DOUBLE PATENTING “[T]he law of obviousness-type double patenting looks to the law of obviousness generally,” such that, “if the later expiring patent is ‘merely an obvious variation of an invention disclosed and claimed in the [reference] patent,’ the later expiring patent is invalid for obviousness-type double patenting.” AbbVie Inc. v. Mathilda and Terence Kennedy Inst. of Rheumatology Trust, 764 F.3d 1366, 1378–79 (Fed. Cir. 2014) (alteration in original) (citing Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340 (Fed. Cir. 2009) and Eli Lilly & Co. v. Teva Parenteral Meds., Inc., 689 F.3d 1368 (Fed. Cir. 2012), and quoting In re Vogel, 422 F.2d 438, 41 (CCPA 1970)). “The non-claim portion of the earlier patent ordinarily does not qualify as prior art against the patentee.” Id. at 1379 (quoting Eli Lilly, 689 F.3d at 1379). “[O]bviousness is not demonstrated merely by showing that an earlier expiring patent dominates a later expiring patent” and “a narrow species can be non-obvious and patent eligible despite a patent on its genus.” Id. However, “not every species of a patented genus is separately patentable,” as they may be anticipated or obvious over the prior art. Id. For example, as is well established in the law of obviousness, where “prior art references ‘provide[d] ample motivation to narrow the [a previously patented] genus . . . to a few [species]’ . . . [the Federal Circuit] concluded that the species at issue . . . was unpatentable.” Id. (first and second alteration in original) Appeal 2015-007511 Application 13/736,931 22 (quoting and citing Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1366, 1372 (Fed. Cir. 2007)). Also well established in the law of obviousness is that “[a] species contained in a previously patented genus may be patentable if the species manifests unexpected properties or produces unexpected results.” Id. at 1380. However, even though “[e]vidence of unexpected results [must] be [considered] . . . even if that evidence was obtained after the patent’s filing or issue date,” Bristol-Myers Squibb Co. v. Teva Pharma. USA, Inc., 769 F.3d 1339, 1342 (Fed. Cir. 2014) (third alteration in original) (denying reh’g en banc) (quoting Genetics Inst., LLC v. Novartis Vaccines Diagnostics, Inc., 655 F.3d 1291, 1307 (Fed. Cir. 2011)), “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention,” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991). “[A]dditional unexpected properties, however, d[o] not upset an already established motivation to modify a prior art compound [or method to make the compound] based on the expected properties of the resulting compound.” Bristol-Myers Squibb Co. v. Teva Pharma. USA, Inc., 752 F.3d 967, 976 (Fed. Cir. 2014) (citing In re Dillon, 919 F.2d 688, 693 (Fed. Cir. 1990)), reh’g en banc denied, 769 F.3d 1339. The Rejection Over Salfeld 813 The Examiner determined that it was obvious to produce an antibody as claimed in Salfeld 813 in CHO cells, and, thus, the antibody of appealed claim 20, based on the disclosure of Ramage. Ans. 5; see also FF1, FF7– FF12. The Examiner also determined that Ramage disclosed, and so, rendered obvious, an antibody-based aqueous (liquid) pharmaceutical Appeal 2015-007511 Application 13/736,931 23 composition (suitable for subcutaneous injection), such as recited by appealed claim 20. FF8–FF11. Beyond Ramage’s teaching and suggestion to use CHO host cells to produce antibodies for human therapy, the Examiner identified other motivation to do so, stating, after citing Goochee and Trill: One of ordinary skill in the art would be motivated to make this modification in order to achieve efficient synthesis of the antibody, and because of the expected convenience expected from using CHO cells, namely the cells are readily transfectable, are able to grow in suspension and serum-free medium, are capable of growth at high densities, have a well-established track record for expressing heterologous gene products, have proven successful in the in the past, offer the use of co-amplification with a number of different selectable genes, offer more human- like glycosylation pattern and offer high level expression. Recombinant expression in CHO cells would provide a source of antibody. Ans. 6; see also FF13–FF19. We find the Examiner has established that the appealed claim is obvious over the claims of Salfeld 813, and Ramage, Goochee, and Trill. Appellants have submitted arguments and associated evidence in the form of literature and declarations under 37 C.F.R. § 1.132.16 Having carefully considered this with the Examiner’s evidence, we find Appellants have not produced evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness-type double patenting are incorrect. Only 16 Mezes Decl.; Declaration Under 37 C.F.R. § 1.132 of Christopher Chumsae, dated Jan. 10, 2014 (“Chumsae Decl.”); and Declaration Under 37 C.F.R. § 1.132 of Dr. Jochen Salfeld, dated Jan. 10, 2014 (“Salfeld Decl.”). Appeal 2015-007511 Application 13/736,931 24 those arguments made by Appellants in the Briefs have been considered in this Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We address Appellants’ arguments below. 1. Appellants’ First Argument: no motivation to use CHO cells Appellants argue that the Salfeld 813 claims do not cover antibodies “produced by CHO cells,” and in 1996 there would be no motivation or expectation of success in selecting CHO cells (particularly over mouse myeloma cells) for such a purpose. App. Br. 15–16. Appellants contend that the skilled artisan would have had a “wide variety of available cellular systems” for producing antibodies, with CHO cells being just one type, without special motivation to select it from among the group and, as support, Appellants cite, inter alia, Jenkins,17 Pietersz,18 Gramer,19 Logan,20 Poul,21 17 Nigel Jenkins et al., Getting the Glycosylation right: Implications for the Biotechnology Industry, 14 NATURE BIOTECH. 975–81 (1996) (“Jenkins”). 18 Geoffrey A. Pietersz et al., In vitro and in vivo Antitumour Activity of a Chimeric Anti-CD19 Antibody, 41 CANCER IMMUNOL. IMMUNOTHER 53–60 (1995) (“Pietersz”). 19 Michael J. Gramer & Charles F. Goochee, Glycosidase Activities of the 293 and NS0 Cell Lines, and of an Antibody-Producing Hybridoma Cell Line, 43 BIOTECH. & BIOENGINEERING 423–28 (1994) (“Gramer”). 20 John S. Logan, Transgeniuc Animals: Beyond ‘Funny Milk,’ 4 CURRENT OP. IN BIOTECH. 591–95 (1993) (“Logan”). 21 Marie-Alix Poul et al., Design of Cassette Baculovirus Vectors for the Production of Therapeutic Antibodies in Insect Cells, 1 IMMNOTECHNOLOGY 189–96 (1995) (“Poul”). Appeal 2015-007511 Application 13/736,931 25 Potter,22 Hiatt 1989,23 Hiatt 1993,24 Shaw,25 Batra,26 Schläpfer,27 Slavin,28 Barnes,29 Page,30 and Ghaderi.31 App. Br. 16–19. Appellants also contend 22 Kathleen N. Potter et al., Antibody Production in the Baculovirus Expression System, 10 INTERN. REV. IMMUNOL. 103–12 (1993) (“Potter”). 23 Andrew Hiatt et al., Production of Antibodies in Transgenic Plants, 342 NATURE 76–78 (1989) (“Hiatt 1989”). 24 Andrew Hiatt & Julian K-C Ma, Characterization and Application of Antibodies Produced in Plants, 10 INTERN. REV. IMMUNOL. 139–52 (1993) (“Hiatt 1993”). 25 Denise R. Shaw et al., Characterization of a Mouse/Human Chimeric Monoclonal Antibody (17-La) to a Colon Cancer Tumor-Associated Antigen, 138 J. IMMUNOLOGY 4534–38 (1987) (“Shaw”). 26 Surinder K. Batra et al., Mouse/Human Chimeric Mel-14 Antibody: Genornic Cloning of the Variable Region Genes, Linkage to Human Constant Region Genes, Expression, and Characterization, 13 HYBRIDOMA 87–97 (1994) (“Batra”). 27 Beatrice S. Schläpfer et al., Development of Optimized Transfectoma Cell lines for Production of Chimeric Antibodies in Hollow Fiber Cell Culture Systems, 45 BIOTECH AND BIOENGINEERING 310–19 (1995) (“Schläpfer”). 28 Dale C. Slavin-Chiarini et al., Biological Properties of Chimeric Domain- deleted Anticarcinoma Immunoglobulins, 55 CANCER RES. 5957–67 (1995) (“Slavin”). 29 Louse M. Barnes et al., Advances in Animal Cell Recombinant Protein Production: GS-NSO Expression System, 32 CYTOTECHNOLOLGY 109–23 (2000) (“Barnes”). While not within the prior art timeframe and, therefore, not particularly relevant and not relied upon in reaching our decision, we note Barnes discloses the extensive use of CHO cells (with some disadvantages), as competition with mouse myeloma cells, as host cells. 30 U.S. Patent No. 5,545,403 (issued Aug. 13, 1996) (“Page”). 31 Darius Ghaderi et al., Implication of the Presence of N- glycollylneuraminic acid in Recombinant Therapeutic Glycoproteins, 28 NATURE BIOTECH. 863–67 (2010) (“Ghaderi”). While not within the prior art timeframe and, therefore, not particularly relevant and not relied upon in our decision, we note Ghaderi does identify an FDA-approved, fully human antibody produced in CHO cells, i.e., Vectibix (panitumumab). Appeal 2015-007511 Application 13/736,931 26 (citing the Mezes Declaration) that, in 1996, CHO cells would not be the choice of host cells “in an industrial setting for use in a liquid pharmaceutical composition.” App. Br. 17; see also id. at 18 (indicating that FDA approval would be a concern in selecting host cells). Appellants also criticize the Examiner’s reliance on Goochee as teaching CHO cells were widely used and appropriate for producing glycoproteins because they are not “the claimed antibody.” App. Br. 21–22. Having considered Appellants’ arguments and evidence, we are not persuaded. Per our claim interpretation, supra, the appealed claim does not require commercialization and/or industrial-scale production and/or FDA- approvability and the skilled artisan’s concerns over such are not relevant or determinative in analyzing obviousness; what is required by the claim is a liquid pharmaceutical composition, i.e., a liquid medicinal drug, that contains the recited antibody produced by CHO cells, with a pharmaceutically acceptable carrier, suitable for subcutaneous injection in a human subject. See claim 20 and claim interpretation discussion, supra. Also, because the opinions set forth in the Mezes Declaration are premised on the skilled artisan having such non-relevant concerns, we do not find this evidence persuasive. See, e.g., Mezes Decl. ¶¶ 12 (“leading to commercial scale manufacturing”), 14 (“in an industrial setting”), 16 (“approved by the FDA”), 17 (“commercial manufacturing . . . capable of high yield, which is essential for production of a therapeutic antibody in an industrial setting”), 18 (“production costs” and “commercial purposes”), 22 (“decreasing levels . . . over time”), 24 (“in an industrial setting”), and 25 (“SUMMARY: . . . in an industrial setting”). Appeal 2015-007511 Application 13/736,931 27 Salfeld 813 claims the same antibody as appealed claim 20, as a pharmaceutical with a pharmaceutically acceptable carrier (FF1, FF7), but not that it was produced with CHO cells, is specifically in liquid form, or is suitable for subcutaneous injection in a human. Ramage teaches and suggests producing such antibodies using CHO cells, and providing the antibodies-so-produced in a liquid pharmaceutical suitable for subcutaneous injection. FF8–FF12. Contrary to Appellants’ contentions, Goochee bolsters the Examiner’s rationale for motivation to use CHO cells to produce antibodies for human therapy, as it identifies that CHO cells do not produce α(1,3)galactosyltransferase such that their (CHO) use would be expected to result in producing proteins (glycoproteins) that do not include α-1,3-Gal, like human cells, and that “[CHO] cells have emerged as the cell line of first choice for the synthesis for recombinant human therapeutic glycoproteins.” FF13–FF16. The Examiner identifies that human anti-TNFα antibodies fall within the group of recombinant therapeutic glycoproteins. Ans. 8–9. Further, the Examiner finds Trill identifies a variety of reasons there would be motivation to use CHO cells as hosts for protein (e.g., mAbs) production. FF17–FF19. Regarding Appellants’ contention that CHO cells were merely one non-obvious option from a variety of host cell types, we are not persuaded. While the references cited by Appellants do identify a variety of host cell types, none of the evidence persuades us that Ramage, Goochee, and Trill would not motivate the skilled artisan to use CHO cells as hosts and, moreover, several of Appellants’ cited references support the Examiner’s position that CHO cells were suitable and/or preferred for the task. For Appeal 2015-007511 Application 13/736,931 28 example, Jenkins indicates that CHO cell lines were used for recombinant protein synthesis (an antibody is a protein), that CHO cell lines can be genetically modified to resemble the human glycan profile, and that CHO cells may prove useful hosts. Jenkins 977. Also, Gramer indicates that “Chinese hamster ovary (CHO) cells have been widely used to produce recombinant glycoproteins.” Gramer 423 (right col.). And, Page discloses that its invention relates to “a CHO cell-line capable of producing a human antibody.” Page Abstract. In view of such disclosures, Appellants’ evidence is inconsistent, at best. 2. Appellants’ Second Argument: the art generally teaches away Appellants argue that “[a] key consideration of any cell line to be used for commercial manufacture of a therapeutic human antibody would be stability, e.g., stable expression of product over 40 or more rounds of cell division. One of ordinary skill would have looked to a cell line capable of high yield, which is essential for production of therapeutic antibody in an industrial setting.” App. Br. 22–23 (quoting Mezes Decl. ¶ 17). In view of this contended consideration, Appellants cite Brown32 and Trill as indicating that CHO cells were insufficient to satisfy the skilled artisan’s desire for high yield and stability and as concluding mouse myeloma cells would be preferred over CHO cells. App. Br. 23–24. Regarding this argument, Appellants also set forth their proposed interpretation of the claim term “pharmaceutical” (or “pharmaceutical composition”), addressed above. App. Br. 25–26. 32 M.E. Brown et al., Process Development for the Production of Recombinant Antibodies using the Glutamine Synthetase (GS) System, 9 CYTOTECHNOLOGY 231–36 (1992) (“Brown”). Appeal 2015-007511 Application 13/736,931 29 We do not find Appellants’ arguments persuasive. As we discussed above, we do not agree with Appellants’ proposed claim interpretation of pharmaceutical (or pharmaceutical composition) — this term does not invoke commercialization and/or industrial scale and/or FDA-approvability concerns. Thus, for this reason alone, Appellants’ related arguments, premised on such contention, that the prior art generally taught away from the use of CHO cells as hosts are not persuasive. However, we also find that neither Brown nor Trill teaches away from the invention or the use of CHO cells as hosts for recombinant antibody production. For example, Brown discloses the use of CHO cells was successful in producing antibodies in significant quantities, in excess of 60 generations. See Brown 232–34 (Tables 1 and 2). This evidences success, even if not via an FDA-approved industrial complex to achieve it. Also, Trill, rather than teaching away from using CHO cells as host cells, identifies several advantages of doing so (as the Examiner found). FF19. 3. Appellants’ Third Argument: teaching away from CHO cells Appellants argue that a CHO cell line disclosed by Ramage for producing the antibody Campath 1H, i.e., 3D11, was discussed in other references as “produc[ing] decreasing levels of Campath over time,” which would make CHO cells an unattractive choice as host cells. App. Br. 26–27 (citing Raper).33 Appellants argue the Mezes Declaration also cites Raper in 33 J. Raper et al., Long Term Stability of Expression of Humanized Monoclonal Antibody Campath 1-H in Chinese Hamster Ovary Cells, 11 Animal Cell Tech.: Developments, Processes, and Products, Biotol Series, European Society of Animal Cell Technology 51-53 (R. Spier, J.B. Griffiths, C. MacDonald, Eds.) (1992) (“Raper”) (citation as provided by Appellants). Appeal 2015-007511 Application 13/736,931 30 concluding “one of ordinary skill in the art in February 1996 would have been motivated to choose a cell line other than CHO for production of the first fully human antibody for therapeutic use in an industrial setting in order to achieve high production levels of HUMIRA®.” App. Br. 28 (emphasis omitted) (quoting Mezes Decl. ¶ 24). Appellants also cite Lifely34 and Isaacs35 as support for the contention that cells other than CHO cells would be preferred to produce Campath 1H due, in part, to “uncertainty” regarding the teachings of Ramage regarding CHO cell production of Campath. App. Br. 29–30. This argument is premised on Appellants’ incorrect claim interpretation, which invokes commercial / industrial / regulatory considerations. For this reason, without more, Appellants’ arguments are not persuasive. Moreover, while Lifely may identify that Y0 cells are preferred over CHO or NS0 cells under certain circumstances, i.e., when the mechanism of lymphocyte depletion in vivo is ADCC rather than monocyte killing activity (without extrapolating to other antibodies), it also identifies that: This antibody [CAMPATH-1H] has been expressed in several mammalian cell lines, including Y0 rat myeloma, NS0 mouse myeloma and Chinese hamster ovary (CHO), grown using different culture conditions, and extensively tested in clinical trials of lymphoproliferative disorders (Hale et al., 1988) and 34 M.Robert Lifely et al., Glycosylation and Biological Activity of CAMPATH-1H Expressed in Different Cell Lines and Grown Under Different Culture Conditions, 5 GLYCOBIOLOGY 813–22 (1995) (“Lifely”). 35 John D. Isaacs et al., Humanised Monoclonal Antibody Therapy for Rheumatoid Arthritis, 340 LANCET 748–52 (1992) (“Isaacs”). Appeal 2015-007511 Application 13/736,931 31 rheumatoid arthritis (Isaacs et al., 1992), with some major successes. Lifely 813, 820. Thus, CHO cells would be reasonably expected to work. And, Isaacs disclosed “[t]herapeutic-grade [CAMPATH-1H] antibody was produced in Chinese hamster ovary cells grown in a hollow-fibre continuous culture system.” Isaacs 748. Therefore, again, CHO cells would be reasonably expected to work. For these reasons, also, we are not persuaded by Appellants’ arguments. Further, Appellants concede, “[w]hile Campath was eventually produced commercially in CHO cells and approved by the FDA, at the time of filing of the instant application there was uncertainty surrounding production of this antibody in CHO cells.” App. Br. 30. “[C]ase law is clear that obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.” Pfizer, 480 F.3d at 1364 (citing In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985)). While we do not rely on Appellants’ concession or the evidence upon which it is based in affirming the Examiner’s rejection, the concession stands for the proposition that Appellants’ evidence does not support the contention that the skilled artisan would be dissuaded from using CHO cells to produce human antibodies for pharmaceuticals. 4. Appellants’ Third Argument: unexpected results Appellants argue the invention of the appealed claim provides unexpected results in producing a human antibody lacking α-1,3-galactose glycan (α-1,3-Gal), thus avoiding potential “severe immune reactions in certain patients.” App. Br. 13, 32; see also Salfeld Decl. ¶ 5. Appellants contend that use of CHO cells to produce anti-TNFα antibodies results in “a Appeal 2015-007511 Application 13/736,931 32 relatively lower risk of causing certain immunogenicity problems in [human] recipients” and “this benefit is unexpected inasmuch as it was not recognized or appreciated in the area as of the priority date.” App. Br. 32. As support, Appellants cite the declarations of Chumsae and Salfeld, and also Mezes, which Appellants contend should have been convincing to the Examiner “[i]f the Examiner had properly construed the claim.” App. Br. 32–34; Reply Br. 18. Appellants’ argument regarding unexpected results can be summarized as follows: post-invention, it was discovered that adalimumab (Humira®), produced in CHO cells, unexpectedly avoids potentially serious immune reactions in patients because the antibodies do not include potentially immunogenic α-1,3-Gal; and, despite the fact that it was known in 199636 that CHO cells naturally do not express α-1,3-galactostransferase and, so, the lack of α-1,3-Gal on polynucleotides produced by CHO cells was expected, there would not have been motivation to use, or an expectation of successfully using, CHO cells to produce therapeutic human antibodies (“to avoid [such] potentially harmful immune responses in human 36 See Goochee (FF13–FF16); Smith (FF25), and Jenkins; see also App. Br. 22–24, 36 (“Appellants do not dispute that it was known in the prior art that CHO cells did not express α-1,3-galactosyltransferase.”) and Reply Br. 15 (“The person of ordinary skill may have even been motivated to try CHO cells given the fact that CHO cells lack α-1,3-galactosyltransferase.”), FF26. Smith discloses that CHO cells only express α-1,3-galactosyltranderase when artificially engineered to do so and, so, normally do not have the capability to transfer Gal from UDP-Gal to the α-1,3-linkage (Smith 3225, 3232) and Jenkins discloses that CHO cell lines used for recombinant protein synthesis have “fortuitously inactivated the gene for α-1,3- galactosyltranferase (Jenkins 977). Appeal 2015-007511 Application 13/736,931 33 patients”) until it was eventually discovered that a potential immunogenic problem existed because of α-1,3-Gal. See e.g., Reply Br. 14–15. The “discovery that a claimed composition possesses a property not disclosed for the prior art subject matter, does not by itself defeat a prima facie case.” In re Dillon, 919 F.2d at 693. “In determining whether the subject matter of a patent claim is obvious, neither the particular motivation nor the avowed purpose of the patentee controls. What matters is the objective reach of the claim. If the claim extends to what is obvious, it is invalid under § 103.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007). Appellants’ position discounts or disregards the fact that other, different, but sufficient motivation to produce Humira® (the antibody constituting the active drug, in the way recited by the appealed claims, i.e., using CHO cells as hosts) did exist in the prior art. Appellants also base their position on considerations for producing an FDA-approved pharmaceutical, on an industrial scale, and for commercial purposes that are not invoked based on the claimed invention. See discussion, supra. “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” In re Baxter, 952 F.2d at 392. While evidence of unexpected results can include post-invention evidence, a potential defect not discovered until after the invention date is not evidence of what a skilled artisan would have expected as of the invention date. Here, the evidence shows that the information the skilled artisan had in 1996 indicated that CHO host cells were a good choice for producing antibodies for human therapy. FF12–FF19, FF22, FF25, FF26, FF28. The fact that, Appeal 2015-007511 Application 13/736,931 34 later, we understand an additional reason why Humira® might be particularly effective is not the type of unexpected result (as much as it is an uncovered latent property) than can overcome a strong case for obviousness as of the invention date, which we have here. See Bristol-Myers, 769 F.3d 1339 (finding later discovered properties of a compound cannot influence prior-existing motivations to use it); see also Bristol-Myers, 752 F.3d at 976 (“additional unexpected properties, however, [do] not upset an already established motivation to modify a prior art compound [or method] based on the expected properties of the resulting compound”). The facts identified in the initial Federal Circuit panel’s decision in Bristol-Myers, 752 F.3d 967, nearly parallel those here. As here, in Bristol- Myers, the claimed invention was found to be obvious. The Bristol-Myers invention was a pharmaceutical compound called “entecavir,” which was a slightly-altered version of a prior art pharmaceutical compound called “2#-CDG,” on which there was evidence, as of the invention date, of praise for its pharmaceutical activity and the promise of therapeutic uses, as well as evidence of the compound’s actual use in research, which showed enough success to warrant the aforementioned praise and related high expectations. Id. at 971–72. Based on this evidence, the Federal Circuit affirmed the district court’s holding that the skilled artisan would have been motivated to modify the prior art compound to form the invention compound and would have had a reasonable expectation of success in so doing. Id. at 972. Evidence showed, however, that years later it was discovered that this prior art compound (2#-CDG) was actually toxic (while, presumably, the invention compound was sufficiently not), which the patentee asserted Appeal 2015-007511 Application 13/736,931 35 would defeat any motivation to use this compound as a starting point. Id. at 974. Further, the patentee asserted that the claimed compound was unexpectedly effective to treat hepatitis B (as well as having a high resistance barrier and a large therapeutic window), without the toxicity issues of the prior art compound. Id. at 977–78. In Bristol-Myers, the Federal Circuit held that the late-discovered unexpected results, while advantageous, did not outweigh the prior-existing motivation to make the invention or the prior-existing reasonable expectation the skilled artisan would have had for successfully so doing. This is the scenario the facts present here, with the exception that, unlike the starting prior art compound eventually found to be toxic and unusable in Bristol-Myers, here the CHO cells, identified as useful and preferred hosts in the prior art, have established themselves as such in the industry. Thus, we find the Examiner presents a strong case for obviousness that is not upset by the late-found, potentially unexpected results. We find this, without more is sufficient to affirm the rejection. However, we also find the declaration evidence relied upon by Appellants unconvincing. As already discussed, above, the Mezes Declaration is premised on an incorrect claim interpretation and, so, is not persuasive. We note the Chumsae Declaration is largely speculative, indicating that “galactose-α-1,3-galactose . . . can increase the immunogenicity of the therapeutic antibodies when administered to human subjects,” that having α-1,3-Gal on an antibody “could lead to dangerous” conditions and it is “highly likely” (or just “likely”) that, were the claimed antibodies produced in a mouse myeloma cell, they would have α-1,3-Gal. Appeal 2015-007511 Application 13/736,931 36 Chumsae Decl. ¶¶ 4, 6, 9, 10 (emphasis added). Chumsae identifies no testing data to confirm this speculation and never states that producing antibodies with CHO cells provides unexpected results. Nor does Chumsae identify prior art evidence that undermines the teachings, discussed above, as to the desirability of using CHO cells to express recombinant antibodies. The Salfeld Declaration does state that “[i]n my opinion, production of human anti-TNFα antibodies using CHO cells, as set forth in the pending claims, results in anti-TNFα antibodies that have unexpected beneficial properties when administered to a human subject, as compared to antibodies produced in other host cell lines, such as mouse myeloma cell line” due to the CHO cells-produced antibodies not “contain[ing] the galactose-α- 1,3,galactose glycan.” Salfeld Decl. ¶ 5. But, like Chumsae, Salfeld’s statements are speculative. Salfeld indicates “[g]lycosylation of thereapeutic antibodies can have a critical effect on immunogencity when administered in humans,” that “production in certain mammalian expression systems can increase the immunogenicity of therapeutic antibodies,” that “humans may produce antibodies against this glycan epitope,” and that all these potential effects present an “increased risk of immunogenicity when administered to humans.” Salfeld Decl. ¶ 6 (emphasis added). Also, the declarants’ use of hedging language to support their opinions underscores the speculative and non-conclusive determinations of the evidence they cite (i.e., Chung, Valliere, Raju, and Ghaderi).37 Chung 37 Christine H. Chung, M.D. et al., Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-α-1,3-Galactose, 358 N. ENGL. J. MED. 1109–17 (2008) (“Chung”); John F. Valliere-Douglass et al., Glutamine-linked and Non-consensus Asparagine-linked Oligosaccharides Present in Human Appeal 2015-007511 Application 13/736,931 37 identifies potential hypersensitivity to the drug cetuximab due to antibodies for galactose-α-1,3-galactose, but indicated that the immunogenic reaction to galactose-α-1,3-galactose is natural in only some people and is also regionally prevalent, suggesting unknown environmental causation. Chung 1115–16. The Examiner also identifies that Chung’s disclosure of glycosylation sites may not support Appellants’ contentions. Ans. 23. Valliere discusses why (or why not) glycosylation resulting in incorporation of galactose-α-1,3-galactose may occur, but does not conclude that inclusion of α-1,3-Gal will lead to dangerous IgE-mediated anaphylaxis in patients. See Valliere, generally. As noted above, it was previously understood that CHO cells do not express α-1,3-galactosyltransferase and that α-1,3-Gal was not detected in CHO cell expression systems. See Smith (FF25) and Jenkins. Raju states, “no evidence in the literature suggests that the presence of α-Gal epitopes on rIgG is immunogenic to humans.” Raju 44. Ghaderi indicates “it is likely that most recombinant therapeutic glycoproteins carry some Neu5Gc” and identifies “the presence of small amounts of Neu5Gc in recombinant glycoproteins produced in CHO cells,” and concludes, “findings suggest that the potential significance of the presence of Neu5Gc on glycoprotein biotherapeutics should be revisited.” Ghaderi 863, 865–66. Thus, none of these references definitively supports Appellants’ contentions, even if they may inferentially do so. Recombinant Antibodies Define Novel Protein Glycosylation Motifs, 285 J. BIO. CHEM. 16012–22 (2010) (“Valliere”); T. Shantha Raju, Glycosylation Variations with Expression Systems and Their Impact on Biological Activity of Therapeutic Immunoglobulins, BIOPROCESS INT’L 44–53 (April 2003) (“Raju”). Appeal 2015-007511 Application 13/736,931 38 Thus, for the reasons above, we are not persuaded by Appellants’ arguments on unexpected results. 5. Appellants’ Fifth Argument: improper reliance on the Salfeld 813 specification Appellants argue that the Examiner improperly relied on the Salfeld 813 specification in “asserting that CHO cells are a preferred system for expressing the recombinant antibodies of the invention.” App. Br. 41 (internal quotation mark omitted). Appellants contend the Examiner used the Salfeld 813 specification as prior art in rejecting appealed claim 20. Id. at 42. We are not persuaded by Appellants’ argument. The Examiner’s mere identification of the stated preference for CHO host cells in the Salfeld 813 specification does not mean the Examiner relied on the same as prior art and it is clear that the Examine did not do so. The Examiner made clear that the specification was reviewed to determine the “coverage” (in the Examiner’s verbiage) of claim 20, which is permissible. See In re Vogel, 422 F.2d 438, 441–42 (CCPA 1970); see also, AbbVie, 764 F.3d at 1380–81 (we may look to an obviousness-type double patenting reference’s disclosure to determine obviousness, to answer whether the claims merely define an obvious variant, and regarding questions of utility). Whether it was necessary to consult the specification of Salfeld 813 to clarify the meaning of any of its claim language or to ascertain the scope of its claims or their relevant utility is, ultimately, irrelevant. The Examiner need not have and did not rely on the Salfeld 813 specification as prior art in rejecting the claims and cited ample other prior art disclosures for this purpose. Appeal 2015-007511 Application 13/736,931 39 For the reasons discussed above, we find the balance of evidence supports the Examiner’s position and affirm the rejection of claim 20 over Salfeld 813. The Rejection Over Salfeld 894 The Salfeld 894 claims, e.g., claim 55 (FF2), are directed to the human antibody of appealed claim 20 and, also, to a pharmaceutical composition including the antibody, suitable for subcutaneous injection. Lacking from the Salfeld 894 claims is an indication that the pharmaceutical was specifically liquid, that the antibody was paired with a pharmaceutically acceptable carrier, suitability for subcutaneous injection, and that the antibody was produced using CHO cells, which are limitations of appealed claim 20. The “liquid,” “carrier,” and “subcutaneous injection” elements are common, but are specifically disclosed by Ramage (FF11) and Le (FF23). The Examiner determined, as set forth above, that Ramage, Goochee, and Trill make the use of CHO cells to produce the antibody obvious. Ans. 54– 58. We find the Examiner has established that the appealed claims would be obvious over the claims of Salfeld 894, and Ramage, Goochee, Trill, and Le. Having carefully considered Appellants’ arguments and evidence, we find Appellants have not produced evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness-type double patenting are incorrect. Only those arguments made by Appellants in the Briefs have been considered in this Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We address Appellants’ arguments below. Appeal 2015-007511 Application 13/736,931 40 Appellants argue claim 20 is not obvious over the claims of Salfeld 894 for the same reasons set forth regarding the claims of Salfeld 813. App. Br. 48–49. Appellants also argue that appealed claim 20 does not recite detectably labeling and conjugating therapeutic moieties to antibodies. Id. at 49. To the extent Appellants’ arguments are duplicative of those made regarding the rejection over the claims of Salfeld 813, we are not persuaded for the reasons set forth above. We agree that appealed claim 20 does not recite labeling, however, it does define the same antibody recited by the claims of Salfeld 894, and producing such antibodies using CHO host cells would be obvious, as discussed above. For the reasons discussed above, we find the balance of evidence supports the Examiner’s position and affirm the rejection of claim 20 over the Salfeld 894 claims. The Rejection Over Salfeld 401 The Salfeld 401 claims, e.g., claim 5 (FF3), are directed to the human antibody of appealed claim 20 and, also, to a pharmaceutical composition including the antibody, and a pharmaceutically acceptable carrier. Lacking from the Salfeld 401 claims is an indication that the pharmaceutical is specifically liquid, that it is suitable for subcutaneous injection, and that the antibody was produced using CHO cells, which are each a limitation of appealed claim 20. The “liquid” and “subcutaneous injection” elements are common, but are specifically disclosed by Ramage (FF11). The Examiner determined, as set forth above, that Ramage, Goochee, and Trill make the use of CHO cells to produce the antibody obvious. Ans. 60–63. Appeal 2015-007511 Application 13/736,931 41 We find the Examiner has established that the appealed claims would be obvious over the claims of Salfeld 401, and Ramage, Goochee, and Trill. Having carefully considered Appellants’ arguments and evidence, we find Appellants have not produced evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness-type double patenting are incorrect. Only those arguments made by Appellants in the Briefs have been considered in this Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We address Appellants’ arguments below. Appellants argue claim 20 is not obvious over the claims of Salfeld 401 for the same reasons set forth regarding the claims of Salfeld 813. App. Br. 51. To the extent Appellants’ arguments are duplicative of those made regarding the rejection over the Salfeld 813 claims, we are not persuaded for the reasons set forth above. For the reasons discussed above, we find the balance of evidence supports the Examiner’s position and affirm the rejection of claim 20 over the Salfeld 401 claims. The Rejection Over Salfeld 761 The Salfeld 761 claims, e.g., claim 79 (FF4), are directed to the human antibody of appealed claim 20 and, also, to a pharmaceutical composition including the antibody, and pharmaceutically acceptable carrier. Lacking from the Salfeld 761 claims is an indication that the pharmaceutical is specifically liquid, that it is suitable for subcutaneous injection, and that the antibody was produced using CHO cells, which are each a limitation of appealed claim 20. The “liquid” and “subcutaneous injection” elements are common, but are specifically disclosed by Ramage (FF11). The Examiner Appeal 2015-007511 Application 13/736,931 42 determined, as set forth above, that Ramage, Goochee, and Trill make the use of CHO cells to produce the antibody obvious. Ans. 65–68. We find the Examiner has established that the appealed claims would be obvious over the claims of Salfeld 761, Ramage, Goochee, Trill, and Gombotz. Having carefully considered Appellants’ arguments and evidence, we find Appellants have not produced evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness- type double patenting are incorrect. Only those arguments made by Appellants in the Briefs have been considered in this Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We address Appellants’ arguments below. Appellants argue claim 20 is not obvious over the claims of Salfeld 761 for the same reasons set forth regarding the claims of Salfeld 813. App. Br. 52. Appellants also argue the ’978 patent (we understand Appellants intended to reference Salfeld 761) claims include a “controlled release” element that its specification does not equate to liquid pharmaceutical compositions of any kind. Id. at 53. To the extent Appellants’ arguments are duplicative of those made regarding the rejection over the Salfeld 813 claims, we are not persuaded for the reasons set forth above. Regarding the issue regarding “controlled release,” we do not find this difference between appealed claim 20 and the Salfeld 761 claims determinative on obviousness. For the reasons discussed above, we find the balance of evidence supports the Examiner’s position and affirm the rejection of claim 20 over the Salfeld 761 claims. Appeal 2015-007511 Application 13/736,931 43 The Rejection Over Salfeld 382 The Salfeld 382 claims, e.g., claim 15 (FF6), are directed to the human antibody of appealed claim 20 and, also, to a pharmaceutical composition including the antibody, and pharmaceutically acceptable carrier. Lacking from the Salfeld 382 claims is an indication that the pharmaceutical is specifically liquid, that it is suitable for subcutaneous injection, and that the antibody was produced using CHO cells, which are each a limitation of appealed claim 20. The “liquid” and “subcutaneous injection” elements are common, but are specifically disclosed by Ramage (FF11). The Examiner determined, as set forth above, that Ramage, Goochee, and Trill make the use of CHO cells to produce the antibody obvious. Ans. 70–73. We find the Examiner has established that the appealed claims would be obvious over the claims of Salfeld 382, and Ramage, Goochee, and Trill. Having carefully considered Appellants’ arguments and evidence, we find Appellants have not produced evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness-type double patenting are incorrect. Only those arguments made by Appellants in the Briefs have been considered in this Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We address Appellants’ arguments below. Appellants argue claim 20 is not obvious over the claims of Salfeld 382 for the same reasons set forth regarding the Salfeld 813 claims. App. Br. 51. To the extent Appellants’ arguments are duplicative of those made regarding the rejection over the claims of Salfeld 813, we are not persuaded for the reasons set forth above. For the reasons discussed above, Appeal 2015-007511 Application 13/736,931 44 we find the balance of evidence supports the Examiner’s position and affirm the rejection of claim 20 over the claims of Salfeld 382. SUMMARY The obviousness-type double patenting rejection over the claims of Salfeld 813, and Ramage, Goochee, and Trill is affirmed. The obviousness-type double patenting rejection over the claims of Salfeld 894, and Le, Ramage, Goochee, and Trill is affirmed. The obviousness-type double patenting rejection over the claims of Salfeld 401, and Ramage, Goochee, and Trill is affirmed. The obviousness-type double patenting rejection over the claims of Salfeld 761, and Gombotz, Ramage, Goochee, and Trill is affirmed. The obviousness-type double patenting rejection over the claims of Salfeld 382, and Ramage, Goochee, and Trill is affirmed. TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED Copy with citationCopy as parenthetical citation