Regeneron Pharmaceuticals, Inc.Download PDFPatent Trials and Appeals BoardOct 27, 20212021001562 (P.T.A.B. Oct. 27, 2021) 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. 15/294,488 10/14/2016 Lynn Macdonald 2010794-1012 3462 103658 7590 10/27/2021 CHOATE/REGENERON c/o CHOATE HALL & STEWART LLP TWO INTERNATIONAL PLACE BOSTON, MA 02110 EXAMINER HILL, KEVIN KAI ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 10/27/2021 ELECTRONIC 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. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): jnease@choate.com patentdocket@choate.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte LYNN MACDONALD, CAGAN GURER, KAROLINA A. MEAGHER, SEAN STEVENS, and ANDREW J. MURPHY ____________ Appeal 2021-001562 Application 15/294,488 Technology Center 1600 ____________ Before DONALD E. ADAMS, CHRISTOPHER G. PAULRAJ, and DAVID COTTA, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims 36–39, 41–43, 45–52, 54–56, and 58 (Final Act.2 2; see also Reply Br.3 2).4 We have jurisdiction under 35 U.S.C. § 6(b). 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as “Regeneron Pharmaceuticals, Inc.” (Appellant’s August 14, 2020, Appeal Brief (Appeal Br.) 2). 2 Examiner’s November 19, 2019, Final Office Action. 3 Appellant’s December 30, 2020, Reply Brief. 4 The transcript for the Oral Hearing held August 10, 2021, was entered into the record August 24, 2021. Appeal 2021-001562 Application 15/294,488 2 We AFFIRM. STATEMENT OF THE CASE Appellant’s claims are drawn to a method of making a nucleic acid that encodes an immunoglobulin light chain variable domain and method for making a human antibody. Appellant’s claims 36, 39, 46, 47, 49, and 52 are reproduced below: 36. A method for making a human antibody, comprising: culturing a host cell comprising a first nucleotide sequence including a first human light chain variable region sequence operably linked to a human heavy chain constant region sequence and a second nucleotide sequence including a second human light chain variable region sequence operably linked to a human light chain constant region sequence, so that a human antibody is expressed from the first and second nucleotide sequences, wherein the first and second human light chain variable region sequences are each a rearranged VL/JL sequence and were identified from a cell of a mouse that includes in its genome: (i) an insertion of one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments upstream of an endogenous mouse light chain constant region sequence, wherein the one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments are operably linked to the endogenous mouse light chain constant region sequence, (ii) an insertion of one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments upstream of an endogenous mouse heavy chain constant region sequence, wherein the one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments are operably linked to the endogenous mouse heavy chain constant region sequence, and Appeal 2021-001562 Application 15/294,488 3 (iii) an inserted nucleic acid sequence that encodes a mouse ADAM6 protein, wherein the mouse ADAM6 protein is expressed from the inserted nucleic acid sequence, and wherein the inserted nucleic acid sequence is between two gene segments included in the one or more unrearranged human VL gene segments and/or one or more unrearranged human JL gene segments upstream of the endogenous mouse heavy chain constant region sequence. 39. The method of claim 36, wherein the method further comprises: (a) exposing the mouse to an antigen of interest, (b) isolating one or more B lymphocytes of the mouse, wherein the one or more B lymphocytes express an antibody that includes the first human light chain variable domain encoded by the first human light chain variable region sequence and the second human light chain variable domain encoded by the second human light chain variable region sequence. 46. The method of claim 36, wherein the host cell is selected from a B cell, a hybridoma, a quadroma, a CHO cell, a COS cell, a 293 cell, a Hela cell, and a human retinal cell expressing a viral nucleic acid sequence. 47. The method of claim 46, wherein the human heavy chain constant region sequence encodes human IgG isotype. 49. The method of claim 47, wherein the human IgG4 is a modified IgG4. 52. A method of making a nucleic acid that encodes an immunoglobulin light chain variable domain comprising: (a) immunizing a mouse with an antigen of interest, wherein the genome of the mouse comprises: Appeal 2021-001562 Application 15/294,488 4 (i) an insertion of one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments upstream of an endogenous mouse light chain constant region sequence, wherein the one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments are operably linked to the endogenous mouse light chain constant region sequence, (ii) an insertion of one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments upstream of an endogenous mouse heavy chain constant region sequence, wherein the one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments are operably linked to the endogenous mouse heavy chain constant region sequence, and (iii) an inserted nucleic acid sequence that encodes a mouse ADAM6 protein, wherein the mouse ADAM6 protein is expressed from the inserted nucleic acid sequence, and wherein the inserted nucleic acid sequence is between two gene segments included in the one or more unrearranged human VL gene segments and/or one or more unrearranged human JL gene segments upstream of the endogenous mouse heavy chain constant region sequence, (b) isolating one or more B lymphocytes of the mouse, wherein the one or more B lymphocytes express an antibody that binds the antigen of interest, and (c) identifying a nucleic acid sequence of a rearranged VL/JL sequence that encodes a light chain variable domain of the antibody of (b) that binds that antigen of interest, wherein the antibody of (b) comprises: (A) two light chains, wherein each light chain comprises a human light chain variable domain and a mouse light chain constant domain, and (B) two heavy chains, wherein each heavy chain comprises a human light chain variable domain and a mouse heavy chain constant domain. Appeal 2021-001562 Application 15/294,488 5 Grounds of rejection before this Panel for review: I. Claims 36–39, 41–43, 45, 46, 51, 52, 54–56, and 58 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Bradley ’192,5 Bradley ’009,6 Shizuya,7 Featherstone,8 Han,9 and Murphy.10 II. Claims 47 and 48 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, and Tanamachi.11 III. Claims 49 and 50 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, Tanamachi, Day,12 and Igawa.13 5 Bradley et al., WO 2011/004192 A1, published Jan. 13, 2011. 6 Bradley et al., WO 2011/158009 A1, published Dec. 22, 2011. 7 Shizuya et al., WO 2009/143472 A2, published Nov. 26, 2009. 8 Karen Featherstone et al., The Mouse Immunoglobulin Heavy Chain V-D Intergenic Sequence Contains Insulators That May Regulate Ordered V(D)J Recombination, 285 J. Biol. Chem. 9327–9338 (2010). 9 Cecil Han et al., Comprehensive Analysis of Reproductive ADAMs: Relationship of ADAM4 and ADAM6 with an ADAM Complex Required for Fertilization in Mice, 80 Biol. Reprod. 1001–1008 (2009). 10 Drew Murphy, BAC-based Modifications of the Mouse Genome: The Big and the Backward, Slide presentation Wellcome Trust Advanced Course: Genetic Manipulation of ES Cells (Nov. 2009). 11 Tanamachi et al., WO 2007/117410 A2, published Oct. 18, 2007. 12 Day, US 2010/0196367 A1, published Aug. 5, 2010. 13 Igawa et al., US 2010/0298542 A1, published Nov. 25, 2010. Appeal 2021-001562 Application 15/294,488 6 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? BACKGROUND “An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen.” Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1250 (Fed. Cir. 2004). “Described in terms of its [protein] structure, an antibody is [typically represented as] . . . a Y-shaped protein consisting of four amino acid chains, two heavy and two light.” Id. Antibody light (L) chains are either κ or λ. The amino terminus of each heavy and light chain contains a variable region (VH and VL, respectively), and the constant region (C) is at the carboxy terminus. The heavy chain constant region (CH) contains the CH1 domain, the hinge region and CH2, CH3 and optionally CH4 domains. The CH2 and CH3 domains make up the Fc region of the heavy chain. The shorter light chain constant region (CL) forms a disulfide-linked association with the CH1 domain of the heavy chain. The two heavy chains are attached via one or more disulfide bonds in the hinge region. Together and alone, the CH1 and CL domains can influence in cis the stability of the paired VH and VL. The Fc region acts in trans to influence the strength of immune system activities by binding to Fc receptors and to provide a long circulating half- life. The heavy chain of the antibody also mediates cell surface display and critical signaling components through B cell development and maturation via membrane and intracellular- signaling sequences that can be alternatively spliced onto CH3 or CH4. (Shizuya 1–2.) For clarity, we reproduce Shizuya’s annotated illustration of a “Standard Antibody” below: Appeal 2021-001562 Application 15/294,488 7 (See Shizuya, Fig. 1.) The forgoing illustration is extracted from Shizuya’s “Figure 1 [and] illustrates the composition of a conventional dimeric antibody . . . comprising light and heavy Ig chains” (Shizuya 12). As Shizuya’s Figure 1 illustrates, each heavy chain protein (non- hashed regions) and light chain protein (hashed regions) comprises a variable region and a constant region. Shizuya’s Figure 1 further identifies the light chain variable region as VL and the light chain constant region as CL. Similarly, Shizuya’s Figure 1 identifies the heavy chain variable region as VH and the heavy chain constant region as CH1-hinge-CH2-CH3. Antibody protein chains are encoded by rearranged nucleic acid derived from un-rearranged genomic nucleic acid (see Roes Decl.14 ¶¶ 5–11 (Roes discusses the art recognized rearrangement of germ-line nucleic acid leading to the production of an antibody and contributing to the diversity of the antibody repertoire.)). Appellant’s Figure 1, reproduced below, 14 Declaration of Jürgen Roes, Ph.D., signed July 19, 2014. Appeal 2021-001562 Application 15/294,488 8 illustrates the art recognized genomic structure of a “Mouse Heavy Chain Locus” and “Human Light Chain Locus”: Appellant’s FIG. 1 illustrates schematics (not to scale) of the mouse heavy chain locus (top) and the human κ light chain locus (bottom). The mouse heavy chain locus is about 3 Mb in length and contains approximately 200 heavy chain variable (VH) gene segments, 13 heavy chain diversity (DH) gene segments and 4 heavy chain joining (JH) gene segments as well as enhancers (Enh) and heavy chain constant (CH) regions. The human κ light chain locus . . . contains about 76 Vκ gene segments, 5 Jκ gene segments, an intronic enhancer (Enh) and a single constant region (Cκ ). (Spec. ¶ 359.) The rearrangement of the various components of the heavy and light chain loci contributes to the diversity of the antibody repertoire, thereby, allowing for the production of antibodies against a diversity of antigens. Appeal 2021-001562 Application 15/294,488 9 Various methods of producing monoclonal antibodies, i.e. a homogeneous antibody population, are known to those of ordinary skill in this art. “One method uses hybridoma technology, which refers to a cloned cell line that produces a single type of antibody. The hybridoma method uses the cells of various species, including mice, hamsters, rats, and humans. . . . Another method uses genetic engineering including recombinant DNA techniques,” which allows for the mixing and matching of various regions of an antibody to produce modified antibodies. Chiron Corp., 363 F.3d at 1250–51. As our reviewing court makes clear, methods of producing genetically modified, i.e. transgenic, mice comprising human immunoglobulin nucleic acid were known in this art prior to Appellant’s claimed invention. See Regeneron Pharms., Inc. v. Merus N.V., 864 F.3d 1343, 1354–55 (Fed. Cir. 2017). In addition, Bradley ’009 discloses the insertion of a human light chain lambda region upstream of a mouse constant region, wherein “[t]his insertion is achieved by gene targeting in [embryonic stem (ES)] cells using techniques well known in the art” (Bradley ’009 35). Similarly, Murphy discloses the “VelocImmune® Solution” that replaces mouse variable regions with human variable regions, retaining all flanking mouse control regions necessary for expression, resulting in the production of chimeric antibodies with human variable domains and mouse constant domains (Murphy 915). Murphy discloses that its chimeric antibodies can be further modified to comprise human constant regions, thus, creating fully-human antibodies (id.). 15 Murphy is not paginated. Therefore, we refer to page numbers as if this document was numbered consecutively beginning with the first page. Appeal 2021-001562 Application 15/294,488 10 Han discloses that “Disintegrin And Metalloprotease (ADAM) family members expressed in male reproductive tissues are divided phylogenetically into three major groups” and “analyzed six ADAMs in one of the groups (ADAMs 4, 6, 24, 26, 29, and 30)” (Han 1001). Murphy discloses that human ADAM6 is a pseudogene (Murphy 23). In contrast, Han discloses that, in mice, ADAM6 is necessary for male mouse fertility (Han 1001). The mouse ADAM6 protein is encoded by genes in immunoglobulin V-D region (Featherstone 9329). Appellant’s independent claim 52, reproduced above, is drawn to a method of making a nucleic acid that encodes an immunoglobulin light chain variable domain. The method of Appellant’s claim 52 comprises the following three steps: (a) immunizing a mouse with an antigen of interest, (b) isolating one or more B lymphocytes of the mouse, wherein the one or more B lymphocytes express an antibody that binds the antigen of interest, and (c) identifying a nucleic acid sequence of a rearranged VL/JL sequence that encodes a light chain variable domain of the antibody of (b) that binds that antigen of interest. Appellant’s claim 52 further requires that the mouse’s genome comprises: (i) an insertion of one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments upstream of an endogenous mouse light chain constant region sequence, wherein the one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments are operably linked to the endogenous mouse light chain constant region sequence, (ii) an insertion of one or more unrearranged human VL gene segments and one or more unrearranged human JL gene Appeal 2021-001562 Application 15/294,488 11 segments upstream of an endogenous mouse heavy chain constant region sequence, wherein the one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments are operably linked to the endogenous mouse heavy chain constant region sequence, and (iii) an inserted nucleic acid sequence that encodes a mouse ADAM6 protein, wherein the mouse ADAM6 protein is expressed from the inserted nucleic acid sequence, and wherein the inserted nucleic acid sequence is between two gene segments included in the one or more unrearranged human VL gene segments and/or one or more unrearranged human JL gene segments upstream of the endogenous mouse heavy chain constant region sequence. In addition, Appellant’s claim 52 requires that the antibody encoded by the nucleic acid comprises: (A) two light chains, wherein each light chain comprises a human light chain variable domain and a mouse light chain constant domain, and (B) two heavy chains, wherein each heavy chain comprises a human light chain variable domain and a mouse heavy chain constant domain. Thus, Appellant’s claim 52 requires the production of a modified chimeric human-mouse antibody, wherein the light chains comprise a human light chain variable domain and a mouse light chain constant domain and the heavy chain comprises a human light chain variable domain and a mouse heavy chain constant domain. Appellant’s independent claim 36 is drawn to a method for making a human antibody. The method of Appellant’s claim 36 comprising the single step of culturing a host cell. Appeal 2021-001562 Application 15/294,488 12 Appellant’s claim 36 requires that the host cell comprises: (1) a first nucleotide sequence including a first human light chain variable region sequence operably linked to a human heavy chain constant region sequence and (2) a second nucleotide sequence including a second human light chain variable region sequence operably linked to a human light chain constant region sequence. Appellant’s claim 36 requires that a human antibody is expressed from the first and second nucleotide sequences. In addition, Appellant’s claim 36 requires that the first and second human light chain variable region sequences are each a rearranged VL/JL sequence. Appellant’s claim 36 further requires that the first and second human light chain variable region sequences were identified, i.e. obtained, from a cell of a mouse that includes in its genome: (i) an insertion of one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments upstream of an endogenous mouse light chain constant region sequence, wherein the one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments are operably linked to the endogenous mouse light chain constant region sequence, (ii) an insertion of one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments upstream of an endogenous mouse heavy chain constant region sequence, wherein the one or more unrearranged human VL gene segments and one or more unrearranged human JL gene segments are operably linked to the endogenous mouse heavy chain constant region sequence, and (iii) an inserted nucleic acid sequence that encodes a mouse ADAM6 protein, wherein the mouse ADAM6 protein is expressed from the inserted nucleic acid sequence, and wherein Appeal 2021-001562 Application 15/294,488 13 the inserted nucleic acid sequence is between two gene segments included in the one or more unrearranged human VL gene segments and/or one or more unrearranged human JL gene segments upstream of the endogenous mouse heavy chain constant region sequence. Thus, the Appellant’s claim 36 requires the production of a modified human antibody, wherein the light chains comprise a human light chain variable domain and a human light chain constant domain and the heavy chain comprises a human light chain variable domain and a human heavy chain constant domain. FACTUAL FINDINGS (FF) We adopt Examiner’s findings concerning the scope and content of the prior art (see Ans.16 3–60), and provide the following for emphasis: FF 1. Examiner identifies the level of ordinary skill in the art as highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.’s and Ph.D’s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, molecular genetics, immunology, and the creation of transgenic organisms. Therefore, the level of ordinary skill in this art is high. (Ans. 11.) FF 2. Bradley ’192 “relates inter alia to non-human animals and cells that are engineered to contain exogenous DNA, such as human immunoglobulin gene DNA, their use in . . . methods for production of non[-]human animals 16 Examiner’s November 2, 2020, Answer. Appeal 2021-001562 Application 15/294,488 14 and cells, and antibodies and antibody chains produced by such animals and derivatives thereof” (Bradley ’192 1; see generally Ans. 4–5). FF 3. Bradley ’192 discloses a non-human mammal whose genome comprises: (a) a plurality of human IgH V regions, one or more human D regions and one or more human J regions upstream of the host non-human mammal constant region; and (b) optionally one or more human Ig light chain kappa V regions and one or more human Ig light chain kappa J regions upstream of the host non-human mammal kappa constant region and/or one or more human Ig light chain lambda V regions and one or more human Ig light chain lambda J regions upstream of the host non-human mammal lambda constant region; wherein the non-human mammal is able to produce a repertoire of chimaeric antibodies or antibody chains having a non-human mammal constant region and a human variable region. (Bradley ’192 4–5; see also Bradley ’009 1–2; Ans. 4–5 and 7.) FF 4. Bradley ’192 discloses the insertion of “some or all of the human light chain V and J regions may be inserted upstream of the heavy chain constant region” (Bradley ’192 13 (emphasis added); see Ans. 4). FF 5. Bradley ’192 discloses a method for producing a fully humanised antibody comprising immunizing a transgenic non-human mammal as above with the desired antigen, recovering the antibody or cells expressing the antibody, and then replacing the non-human mammal constant region with a human constant region. This can be done by standard cloning techniques at the DNA level to replace the non-human mammal constant region with an appropriate human constant region DNA sequence. (Bradley ’192 22; see generally Ans. 4–5.) Appeal 2021-001562 Application 15/294,488 15 FF 6. Bradley ’009 relates to a non-human mammal or a cell whose genome additionally or alternatively comprises a plurality of human Ig light chain V regions, and one or more human J regions upstream of a host non-human mammal heavy chain constant region, such that the cell or mammal is able to express a chimaeric antibody chain. The cell or mammal may be able to express an antibody having both heavy and light chains, including at least one chimaeric antibody chain. (Bradley ’009 14; see also id. 5 (Bradley ’009 discloses “methods for the construction of chimaeric human heavy and light chain loci in a non-human mammal, for example a mouse”); see Ans. 5–6.) FF 7. Bradley ’009 discloses a: cell or non-human mammal . . . encod[ing] an antibody comprising an antibody chain having a human heavy chain variable region upstream of a mouse light chain constant region, or an antibody chain having a human light chain variable region upstream of a mouse heavy chain constant region, in combination with one of: a fully human antibody light chain; a fully human antibody heavy chain; a non-human vertebrate (e.g., mouse or rat) antibody light chain; a non-human vertebrate (e.g., mouse or rat) antibody heavy chain; a chimaeric non-human vertebrate (e.g., mouse or rat)- human antibody chain; an antibody chain having a human heavy chain variable region upstream of a non-human vertebrate (e.g., mouse or rat) light chain constant region; Appeal 2021-001562 Application 15/294,488 16 an antibody chain having a human light chain variable region upstream of a non-human vertebrate (e.g., mouse or rat) heavy chain constant region. (Bradley ’009 14 (emphasis added); see also Bradley ’009 35 (Bradley ’009 discloses the insertion of the human light chain lambda region upstream of the mouse constant region, wherein “[t]his insertion is achieved by gene targeting in [embryonic stem (ES)] cells using techniques well known in the art”); Ans. 5–6.) FF 8. Shizuya discloses that Antibody light (L) chains are either κ or λ. The amino terminus of each heavy and light chain contains a variable region (VH and VL, respectively), and the constant region (C) is at the carboxy terminus. The heavy chain constant region (CH) contains the CH1 domain, the hinge region and CH2, CH3 and optionally CH4 domains. The CH2 and CH3 domains make up the Fc region of the heavy chain. The shorter light chain constant region (CL) forms a disulfide-linked association with the CH1 domain of the heavy chain. The two heavy chains are attached via one or more disulfide bonds in the hinge region. Together and alone, the CH1 and CL domains can influence in cis the stability of the paired VH and VL. The Fc region acts in trans to influence the strength of immune system activities by binding to Fc receptors and to provide a long circulating half- life. The heavy chain of the antibody also mediates cell surface display and critical signaling components through B cell development and maturation via membrane and intracellular- signaling sequences that can be alternatively spliced onto CH3 or CH4. (Shizuya 1–2; see generally Ans. 8.) FF 9. Shizuya “relates generally to single variable domain antibodies having a light chain variable domain (VL), and more specifically to single VL domain antibodies comprising a human VL domain, methods of making, Appeal 2021-001562 Application 15/294,488 17 methods of use and transgenic non-human cells and animals producing such antibodies” (Shizuya 1; see generally Ans. 8). FF 10. Shizuya discloses a “non-human mammalian cell [having] . . . a genome comprising [a] human [light chain V region] operably linked to a non-human heavy chain C region, wherein the human VL and J gene segments replace an endogenous VH domain” (Shizuya 6; see generally Ans. 8). FF 11. Shizuya discloses a “single variable domain antibody” (SVD antibody)[, which] refer[s] to either a monomer or a dimer of a single Ig chain having a V domain and a C domain. In particular, “single VL domain antibody” or “SVLD antibody” refers to an SVD antibody wherein the V domain is derived from an Ig light chain. (Shizuya 15.) FF 12. Shizuya discloses “[s]ingle chain antibodies comprising a VL domain rather than a VH . . . domain are entirely new type of antibod[y] with new repertoires of diversity” (Shizuya 24). FF 13. Shizuya discloses that “[a]ntigen-specific repertoires can be recovered from immunized mice by hybridoma technology, single-cell RT- PCR for selected B cells, by antibody display technologies, and other methods known in the art” (Shizuya 28). FF 14. Murphy discloses the “VelocImmune® Solution” that replaces mouse variable regions with human variable regions, retaining all flanking mouse control regions necessary for expression, resulting in the production of chimeric antibodies with human variable domains and mouse constant domains and that its chimeric antibodies can be further modified to comprise human constant regions, thus, creating fully-human antibodies (Murphy 9). Appeal 2021-001562 Application 15/294,488 18 FF 15. Examiner finds that the combination of Bradley ’192, Bradley ’009, and Shizuya does not disclose a transgenic non-human animal comprising “an inserted nucleic acid sequence that encodes a mouse ADAM6 protein” (Ans. 8). FF 16. Featherstone discloses that the mouse “V-D region encodes two genes, Adams6a and Adam6b (a distintegrin and metalloproteinase domain 6a and –b)” (Featherstone 9329; see Ans. 8). FF 17. Han discloses that “Disintegrin And Metalloprotease (ADAM) family members expressed in male reproductive tissues are divided phylogenetically into three major groups” and “analyzed six ADAMs in one of the groups (ADAMs 4, 6, 24, 26, 29, and 30)” (Han 1001; see generally Ans. 8–9). FF 18. Han “found that the levels of ADAM4 and ADAM6 are dramatically reduced in Adam2 and Adam3 knockout sperm defective in various fertilization processes” and disclosed the “involvement of ADAM4 and ADAM6 in a reproductive ADAM system that functions in fertilization” (Han 1001; see generally Ans. 8–9). FF 19. Murphy disclosed that male fertility can be restored in transgenic mice that comprise a human immunoglobulin genome by introducing murine ADAM6, i.e. “ADAM6 ‘Re-murinization’,” into the human immunoglobulin V-D region (Murphy 26; see also id. at 23 (Murphy discloses that the “human [] ADAM6 is a pseudogene”); Ans. 9). FF 20. Examiner finds that the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy do not disclose a “humanized antibody [that] comprises a human IgG isotype” (Ans. 54). Appeal 2021-001562 Application 15/294,488 19 FF 21. Tanamachi discloses antibody gene constructs and that “[p]referred constant region isotypes present in the expression vectors include human IgG1 and IgG4 constant regions for the heavy chain and the human kappa constant region for the light chain” (Tanamachi 21; Ans. 54). FF 22. Examiner finds that the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, and Tanamachi does not disclose a “humanized antibody [that] comprises a modified human IgG4 isotype, nor wherein said modification is a substitution in the hinge region” (Ans. 58). FF 23. Examiner relies on Day to disclose “a modified IgG4, wherein humanized heavy chain constant domains may be altered to modify the properties of the antibody, e.g. increase or decrease Fc receptor binding, antibody glycosylation, effector cell function, or complement function” (Ans. 58 (citing Day ¶ 58)). FF 24. Examiner relies on Igawa to disclose “a method of generating antibodies, wherein the IgG4 isotype is modified in the hinge region via substitutions . . ., thereby achieving improved physiochemical properties such as stability, homogeneity, immunogenicity, safety, [and] pharmacokinetics” (Ans. 58 (citing Igawa ¶¶ 34, 35, 98, and 145)). ANALYSIS Rejection I: The evidence on this record supports a finding that, prior to Appellant’s claimed invention, methods of making human antibodies in transgenic animals and host cells were known in this art (see FF 1–14). The evidence on this record supports a finding that, prior to Appellant’s claimed invention, those of ordinary skill in this art recognized that antibodies can be Appeal 2021-001562 Application 15/294,488 20 modified into any number of different configurations, including a configuration wherein a host cell or non-human mammal encodes an antibody comprising an antibody chain having a human light chain variable region upstream of a mouse heavy chain constant region in combination with a fully human antibody light chain (FF 7). In addition, the evidence of record supports a finding that mouse antibody variable and/or constant regions, i.e. may be replaced with human antibody variable and/or constant regions (see FF 1–14). Thus, the evidence of record supports a conclusion that the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy makes obvious a method of culturing a host cell comprising: a first nucleotide sequence including a first human light chain variable region sequence operably linked to a human heavy chain constant region sequence and a second nucleotide sequence including a second human light chain variable region sequence operably linked to a human light chain constant region sequence, as recited in Appellant’s claim 36. As discussed above, prior to Appellant’s claimed invention, those of ordinary skill in this art recognized that transgenic animals, containing nucleic acid encoding human immunoglobulin regions, are capable of producing functional fully human or chimeric human–non-human antibodies (FF 1–14). The evidence of record establishes that these antibodies contain antibody light chains resulting from the rearrangement of VL/JL genomic sequences (id.). The evidence of record further establishes that the foregoing transgenic animals may be immunized against a particular antigen, antibody producing cells may be isolated from the transgenic animal, and the isolated cells may be grown in culture. See FF 1–14; see also Chiron Corp., 363 F.3d at 1250–51; Regeneron Pharms., Inc., 864 F.3d at 1354–55. Appeal 2021-001562 Application 15/294,488 21 The evidence of record further supports a finding that, prior to Appellant’s filing date, those of ordinary skill in this art would have recognized that producing fertile male mice containing human immunoglobulin genomic regions would require the insertion of nucleic acid encoding a functional mouse ADAM6 protein into the region between the human VL and JL immunoglobulin genomic sequence (see FF 16–19). In sum, the combination of prior art relied upon by Examiner suggests methods for making a human antibody, and a nucleic acid that encodes an immunoglobulin light chain variable domain, as set forth in Appellant’s claimed invention, and would have motivated those of ordinary skill in this art to follow, with a reasonable expectation of success, the guidance set forth in the prior art to develop diverse antibodies, while maintaining the fertility of male mice containing such a modified immunoglobulin genome. For the foregoing reasons, we find no error in Examiner’s conclusion that, at the time Appellant’s invention was made, the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy makes obvious the subject matter of Appellant’s claimed invention. Appellant’s separate arguments with respect to claims 36, 39, and 52 are addressed below: Claim 36: Appellant’s claim 36 is reproduced above. The rejection before this Panel is based on obviousness, not anticipation. Therefore, we are not persuaded by Appellant’s contention that “[t]here is no allegation that any one of the cited references in and of itself discloses a method as set forth in the present claims” (Appeal Br. 18). Appeal 2021-001562 Application 15/294,488 22 For the foregoing reasons, we are not persuaded by Appellant’s contention that “Examiner has relied on disparate, selected, teachings from individual references and concluded that one of skill in the art would [have been] . . . motivated to combine the references with a reasonable expectation of success” (id.; cf. FF 1–19). As discussed above, Bradley ’009 expressly discloses a “cell or non- human mammal . . . encod[ing] an antibody comprising an antibody chain having . . . a human light chain variable region upstream of a mouse heavy chain constant region, in combination with . . . a fully human antibody light chain,” (FF 7). As further discussed above, the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy makes obvious the substitution of a human heavy chain constant region for a mouse heavy chain constant region or in the alternative the substitution of a mouse heavy chain constant region for a human heavy chain constant region (see FF 1– 14). Therefore, we are not persuaded by Appellant’s contention that “Examiner’s position overlooks the number of choices that must be made, without any guidance whatsoever from [Bradley ’009] . . . as to which immunoglobulin chains to select from the categories on page 14 to reach the recited combination” (Reply Br. 6; see also id. at 7). “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put into the last opening in a jig- saw puzzle. It is not invention.” Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 335 (1945); see also Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (“Disclos[ure of] a multitude of effective combinations does not render any particular formulation less obvious.”). Appeal 2021-001562 Application 15/294,488 23 We are not persuaded by Appellant’s contention that the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy “does not provide any disclosure that two immunoglobulin light chains that each comprise a human light chain variable domain and a mouse light chain constant domain could actually pair with two immunoglobulin chains that each comprise a human light chain variable domain and a mouse heavy chain constant domain” (Appeal Br. 19). As Shizuya explains, “[t]he shorter light chain constant region (CL) forms a disulfide-linked association with the CH1 domain of the heavy chain. The two heavy chains are attached via one or more disulfide bonds in the hinge region” (FF 8). Appellant failed to provide persuasive evidence or argument to support a finding that an antibody variable region will prevent the disulfide-linked association of heavy and light chain constant regions, as disclosed by Shizuya (see id.). Roes declares that “prior to the above-identified application, I am not aware of any homologous recombination resulting in the substitution of one or more VH, DH, and JH gene segments with VL and/or JL gene segments” and that “I would have questioned whether a heavy chain immunoglobulin locus modified to have a cluster of unrearranged VL and or [JL] gene segments in place of the endogenous VH, DH and/or JH segments would be able to recombine and form a functional immunoglobulin heavy chain gene” (Roes Decl. ¶¶ 14–15; see also Appeal Br. 21; Reply Br. 8). Roes further states: Although there is some indication that human VH regions are capable of the essential interaction with murine surrogate light chains in vivo, to my knowledge there is no substantive information available on the interactions between human VL regions and murine [host] surrogate light chains. Indeed, one report indicates that, human surrogate light chains do not Appeal 2021-001562 Application 15/294,488 24 interact with murine VL regions. See, Hirabayashi et al. (1995) J. Immunol. 155:1218-28. Accordingly, there would be no reason to expect efficient interaction between VL regions, particularly human VL regions, and mouse surrogate light chains in vivo. (Roes Decl. ¶ 16; see also Reply Br. 14). Roes makes no mention of Bradley ’009, which expressly discloses a non-human mammal encoding an antibody comprising a light chain variable region operatively linked to a heavy chain constant region (see FF 7). Thus, we are not persuaded by Appellant’s contention that “Examiner’s argument attributes guidance to select the claimed combination of hybrid and light chain loci where none can be found” (Appeal Br. 21). In addition, because Roes fails to acknowledge the disclosure of Bradley ’009, either alone or in combination with Bradley ’192, Shizuya, Featherstone, Han, and Murphy, we find that the preponderance of evidence falls in favor of Examiner (see FF 1–14). Murphy Declaration also fails to acknowledge the disclosure of Bradley ’009, either alone or in combination with Bradley ’192, Shizuya, Featherstone, Han, and Murphy and, thus, Murphy Declaration’s discussion of antibodies comprising variable light regions operably linked to heavy constant regions is not persuasive (see Murphy Decl. 17 ¶ 3). In addition, we find that Roes’ speculation on the interaction of murine surrogate light chains with human VL regions, based on a report that human surrogate light chains do not interact with murine VL regions lacks an evidentiary foundation on this record (Roes Decl. ¶ 16). In addition, Roes’ speculation runs counter to the reasonable expectation of success provided by Bradley ’009, either alone or in combination with Bradley ’192, 17 Declaration of Andrew Murphy, Ph.D., signed July 16, 2014. Appeal 2021-001562 Application 15/294,488 25 Shizuya, Featherstone, Han, and Murphy. To be clear, prior art is presumed to be enabled. See In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012) (“[A] prior art printed publication cited by an examiner is presumptively enabling barring any showing to the contrary by a patent applicant or patentee.”). Moreover, absolute predictability of success is not required for obviousness. See In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988) (“Obviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success.”). Thus, we find that the preponderance of evidence on this record falls in favor of Examiner. Because obviousness does not require absolute predictability of success, we are not persuaded by Roes’ statement that “the outcome of replacing the mouse VH gene region with a VL gene region would have been difficult to predict with any certainty, and concerns as to functionality of such a locus would have been valid” (Roes Decl. ¶ 16 (emphasis added); see also Appeal Br. 21 (citing Roes Decl. ¶¶ 15–16)). Thus, for the foregoing reasons, we find that Roes’ statement is outweighed by the preponderance of evidence on this record supporting a reasonable expectation of success (see FF 7; see also FF 1–6 and 8–14). For the foregoing reasons, we are not persuaded by Roes’ speculation on whether regulatory elements would function properly when a VH, DH, and/or JH region is replaced with VL and JL region (see Roes Decl. ¶ 17; cf. FF 7; see also FF 1–6 and 8–14). Thus, we find that the preponderance of evidence on this record falls in favor of Examiner. Therefore, we are not persuaded by Roes’ statement that “[t]he overall efficient generation of B Appeal 2021-001562 Application 15/294,488 26 cells [resulting in Appellant’s claimed antibodies] is in my view unexpected” (Roes Decl. ¶ 17; see also id. ¶ 18). For the foregoing reasons, we are not persuaded by Appellant’s contention that the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy teaches away from Appellant’s claimed invention, because it also makes obvious additional antibody modifications (Appeal Br. 18–19; see id. at 20 (Appellant contends that Bradley ’009 “describes every possible combination of a human or non-human variable domain with a human or non-human constant domain to form an immunoglobulin chain”) (footnote omitted); see also Reply Br. 5 and 12– 13). See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004) (“The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed”). In addition, notwithstanding Appellant’s contentions to the contrary, we find that the alternatives suggested by the combination of evidence relied upon by Examiner amplifies the obviousness of Appellant’s claimed invention and the recognition of those of ordinary skill in this art that, at the time of Appellant’s claimed invention, antibody domains could have been mixed and matched, rather routinely, with a reasonable expectation that functional antibody would have been successfully obtained. Therefore, we are not persuaded by Appellant’s contention that the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy “cannot support an obviousness rejection of the present claims, which include a specific immunoglobulin structure resulting in a particular antibody format” (Appeal Br. 20). See In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. Appeal 2021-001562 Application 15/294,488 27 1986) (Each reference “must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.”); see also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”); Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1364 (Fed. Cir. 2012) (The claim “recites a combination of elements that were all known in the prior art, and all that was required to obtain that combination was to substitute one well-known . . . agent for another.”). Thus, we are not persuaded by Appellant’s contention that the evidence relied upon by Examiner teaches away from Appellant’s claimed invention (see Appeal Br. 23–26; see also Reply Br. 7–8). For the foregoing reasons, we are not persuaded by Appellant’s contentions that the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy does not support a conclusion of obviousness, because paragraph 6 on page 13 of Bradley ’192 “does not disclose that the modification is being made in a mouse or that the heavy chain constant region is a mouse heavy chain constant region” (Reply Br. 9; see id. (Appellant contends that “Shizuya does not describe an actual reduction to practice of any transgenic animal modified to express its single VL domain antibodies”); id. at 11 (Appellant contends that “it is inaccurate to state (or even suggest) that any of [Bradley ’192, Bradley ’009,] . . . or Shizuya ‘successfully reduced to practice’ a non-human cell or animal having [the] features” set forth in Appellant’s claimed invention)). As discussed above, the rejection before this panel is obviousness, not anticipation, and, thus, each reference “must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.” Merck, Appeal 2021-001562 Application 15/294,488 28 800 F.2d 1091, 1097; see also In re Susi, 440 F.2d 442, 446 n.3 (CCPA 1971) (Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or non-preferred embodiments.); In re Lamberti, 545 F.2d 747, 750 (CCPA 1976) (A reference disclosure is not limited only to its preferred embodiments, but is available for all that it discloses and suggests to one of ordinary skill in the art.). For the foregoing reasons, we are not persuaded by Appellant’s contentions concerning “the number of possible chimeric combinations” suggested by the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy (see Appeal Br. 20–21). To be clear, and as discussed above, the evidence on this record, as well as case law, establishes that, prior to Appellant’s claimed invention, those of ordinary skill in this art understood that antibodies have a: (a) variable region that recognizes antigen and (b) constant region. The evidence of record, and case law, also supports a finding that those of ordinary skill in this art understood, prior to the filing date of Appellant’s claimed invention, that a variable region could be placed on the constant region of an immunoglobulin of a different species, e.g. a human variable region on a mouse constant region, resulting in a chimeric antibody. See FF 1–14; see also Chiron Corp., 363 F.3d at 1250–51. Simply stated, the foregoing types of antibody modifications are not new, unpredictable, non-obvious, nor are they beyond the skill of those of ordinary skill in this art. Contrary to Appellant’s contentions: If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the Appeal 2021-001562 Application 15/294,488 29 technique is obvious unless its actual application is beyond his or her skill. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007). In addition, the evidence of record makes clear that those of ordinary skill in this art would have been motivated to modify antibodies using techniques known in the art with the reasonable expectation of successfully enhancing the diversity of the antibody repertoire (see FF 12 (Shizuya discusses a particular type of antibody modification, specifically single chain antibodies, which results in an “entirely new type of antibod[y] with new repertoires of diversity”); see also Roes Decl. ¶ 9 (Roes discusses additional means of creating antibody diversity)); O’Farrell, 853 F.2d at 903 (“Obviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success.”). As discussed above, the evidence of record further supports a finding that, prior to Appellant’s filing date, those of ordinary skill in this art would have recognized that producing fertile male mice containing human immunoglobulin genomic regions would require the insertion of nucleic acid encoding a functional mouse ADAM6 protein into the region between the human VL and JL immunoglobulin genomic sequence (see FF 16–19). For the foregoing reasons, we are not persuaded by Appellant’s contention that “Examiner . . . offered no objective evidence in support for its position that light chain variable region genes are ‘analogous’ in context to heavy chain variable region genes, and ignores the fact that the variable region loci of heavy chains and light chains have different sequences and structures” (Appeal Br. 21). On this record, inserting a gene that encodes ADAM6, which is normally located in the region of the mouse genome that encodes the mouse Appeal 2021-001562 Application 15/294,488 30 heavy chain variable region and is necessary for male fertility in mice, into the genome of a transgenic mouse that encodes a human light chain variable region would have been obvious to those of ordinary skill in this art. Murphy supports a finding that there would have been a reasonable expectation of success in making a similar modification (see FF 19). When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that is was obvious under § 103. See KSR, 550 U.S. at 421. “A person of ordinary skill is also a person of ordinary creativity, not an automaton.” Id. at 421. Thus, it is proper to “take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 418. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 425 (CCPA 1981). For the foregoing reasons, we are not persuaded by Appellant’s contention that the combination of Bradley ’192, Bradley ’009, and Shizuya teaches away from Appellant’s claimed invention in favor of single chain antibodies and doing otherwise would “destroy the entire purpose of Shizuya” (see Appeal Br. 24–27). For the foregoing reasons, we are not persuaded by Appellant’s contention that Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Appeal 2021-001562 Application 15/294,488 31 Murphy fails to provide a reasonable expectation of success (Appeal Br. 27– 30 (citing Roes Decl. ¶¶ 15–17); see also Reply Br. 13–16). For the foregoing reasons, we are not persuaded by Appellant’s contention that there was no motivation to combine Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy or that Examiner relied upon improper hindsight (see Appeal Br. 23; see also Reply Br. 12). For the reasons discussed above, we are not persuaded by Roes statements regarding unexpected results (see Appeal Br. 30 (citing Roes Decl. ¶ 13)). Further, in order to be persuasive of non-obviousness, “[e]vidence of secondary considerations must be reasonably commensurate with the scope of the claims.” In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). Murphy states that “[s]urprisingly, the mice described in the instant application are capable of generating VL binding proteins that specifically bind small molecules at a rate higher than that seen for binding- antibody production in VelocImmune® (V13) mice” (Murphy ¶ 7). Appellant’s claimed invention is not limited to the production of antibodies that recognize small molecules. Therefore, we are not persuaded by Appellant’s contentions relating to antibodies that bind small molecules (see Appeal Br. 30–31 (citing Murphy Decl. ¶¶ 3 and 7)). Claim 39: Appellant’s claim 39 is reproduced above. Appellant incorporates its arguments with respect to claim 36 by reference. For the reasons discussed above, with respect to Appellant’s claim 36, we are not persuaded. Appeal 2021-001562 Application 15/294,488 32 Further, for the reasons discussed above, we are not persuaded by Appellant’s contention that the lack of any teaching or suggestion in the cited references of a pairing of immunoglobulin chains that both include human light chain variable domains, as well as the evidence of secondary considerations that such a pairing provides unexpected results, . . . weigh heavily in favor of the patentability of claim 39. (Appeal Br. 32; see Reply Br. 17.) Claim 52: Appellant’s claim 52 is reproduced above. Appellant contends: Further, similar to claim 39 discussed above, claim 52 expressly recites that the genetically modified mouse expresses an antibody formed, in part, due to unexpected pairing of a light chain variable domain with another light chain variable domain: “the antibody comprises: (A) two light chains, wherein each light chain comprises a human light chain variable domain and a mouse light chain constant domain, and (B) two heavy chains, wherein each heavy chain comprises a human light chain variable domain and a mouse heavy chain constant domain.” Thus, the failure of the cited references to teach a pairing of immunoglobulin chains that both include human light chain variable domains, as well as the evidence of secondary considerations that such a pairing provides unexpected results, are highly relevant and evidence the patentability of claims 52, 54-56, and 58. (Appeal Br. 33–34 (emphasis omitted); see also Reply Br. 17.) For the reasons discussed above, we are not persuaded. Appeal 2021-001562 Application 15/294,488 33 Rejection II: Appellant’s claim 47 is reproduced above. Examiner finds that the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy does not disclose a “humanized antibody [that] comprises a human IgG isotype” and relies on Tanamachi to make up for this deficiency (see FF 1–21). We find no error in Examiner’s conclusion that, at the time Appellant’s claimed invention was made, the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, and Tanamachi makes obvious the subject matter of Appellant’s claim 47. Having found no deficiency in the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy we are not persuaded by Appellant’s contention that Tanamachi fails to make up for Appellant’s alleged deficiencies (Appeal Br. 34; see also Reply Br. 18). For the same reasons, we are not persuaded by Appellant’s contention that the references relied upon by Examiner teach away from Appellant’s claimed invention (Appeal Br. 34). Further, as discussed above, an antibody’s Fc region acts in trans to influence the strength of immune system activities by binding to Fc receptors and to provide a long circulating half-life. The heavy chain of the antibody also mediates cell surface display and critical signaling components through B cell development and maturation via membrane and intracellular-signaling sequences that can be alternatively spliced onto CH3 or CH4. (FF 8.) Thus, those of ordinary skill in this art would have recognized, prior to Appellant’s claimed invention, that the choice of Fc portion of an antibody’s heavy chain is important to impart effector functions to the Appeal 2021-001562 Application 15/294,488 34 antibody. See In re Sovish, 769 F.2d 738, 743 (Fed. Cir. 1985) (Skill in the art is presumed.). Examiner relies on Tanamachi to make obvious, inter alia, the selection of the human IgG1 and IgG4 heavy chain constant regions (see FF 21). Therefore, we are not persuaded by Appellant’s contention that “it is difficult to understand how a person of ordinary skill reviewing these references would have been motivated to pick and choose amongst the various options to reach the claimed method, as the Examiner contends” (Appeal Br. 34). We are also not persuaded by Appellant’s contention that Tanamachi is inapplicable because the reference does not disclose a variable light chain operatively linked to a heavy chain, a transgenic mouse encoding such an antibody, or methods of making an antibody using such a mouse, which are accounted for in the contribution of the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy to the rejection (Appeal Br. 35). Rejection III: Appellant’s claim 49 is reproduced above. Examiner finds that the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, and Tanamachi does not disclose a “humanized antibody [that] comprises a modified human IgG4 isotype, nor wherein said modification is a substitution in the hinge region” and relies on Day and Igawa to make up for this deficiency (see FF 1–24). We find no error in Examiner’s conclusion that, at the time Appellant’s claimed invention was made, the combination of Bradley ’192, Bradley ’009, Appeal 2021-001562 Application 15/294,488 35 Shizuya, Featherstone, Han, Murphy, Tanamachi, Day, and Igawa makes obvious the subject matter of Appellant’s claim 49. Having found no deficiency in the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, and Tanamachi we are not persuaded by Appellant’s contention that Day and Igawa fails to make up for Appellant’s alleged deficiencies (Appeal Br. 36; see also Reply Br. 18). As discussed above, the evidence on this record supports a finding that the production of antibodies in transgenic mice was known in this art prior to the filing date of Appellant’s claimed invention. See FF 1–14; see also Chiron Corp., 363 F.3d at 1250–51; Regeneron Pharms., Inc., 864 F.3d at 1354–55. Therefore, we are not persuaded by Appellant’s contention that “Day and Igawa . . . are silent on using a mouse as a platform for antibody production” (Appeal Br. 36). For the reasons discussed above, the evidence of record supports a finding that, prior to the filing date of Appellant’s claimed invention, those of ordinary skill in this art would have found it prima facie obvious to mix and match antibody variable and constant regions, including the combination of a human light chain variable region with a human heavy chain constant region (see FF 1–14). Thus a person of ordinary skill in this art would have found it prima facie obvious to use the human IgG constant region made obvious by Day and Igawa in the antibody made obvious by the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, and Tanamachi, specifically an antibody comprising a human light chain variable region operably linked to a human IgG constant region to achieve Appeal 2021-001562 Application 15/294,488 36 the benefits disclosed by Day and Igawa (see FF 1–24). Thus, we are not persuaded by Appellant’s contentions to the contrary (see Appeal Br. 36). CONCLUSION The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. Rejection I: The rejection of claims 36, 39, and 52 under 35 U.S.C. § 103(a) as unpatentable over the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, and Murphy is affirmed. Claims 37, 38, 41–43, 45, 46, 51, 54–56, and 58 are not separately argued and fall with claim 36. Claims 54–56, and 58 are not separately argued and fall with claim 52. Rejection II: The rejection of claim 47 under 35 U.S.C. § 103(a) as unpatentable over the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, and Tanamachi is affirmed. Claim 48 is not separately argued and fall with claim 47. Rejection III: The rejection of claim 49 under 35 U.S.C. § 103(a) as unpatentable over the combination of Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, Tanamachi, Day, and Igawa is affirmed. Claim 50 is not separately argued and fall with claim 49. Appeal 2021-001562 Application 15/294,488 37 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 36–39, 41–43, 45, 46, 51, 52, 54–56, 58 103(a) Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy 36–39, 41–43, 45, 46, 51, 52, 54–56, 58 47, 48 103(a) Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, Tanamachi 47, 48 49, 50 103(a) Bradley ’192, Bradley ’009, Shizuya, Featherstone, Han, Murphy, Tanamachi, Day, Igawa 49, 50 Overall Outcome 36–39, 41–43, 45– 52, 54–56, 58 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). See 37 C.F.R. § 1.136(a)(1)(iv) (2019). AFFIRMED Copy with citationCopy as parenthetical citation