Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 3-13 and 15-19 are pending and currently under prosecution.
Claim Objections
Claim 11 is objected to because of the following informalities: Claim 11 recites “The use of claim 3, wherein the second TYRP-1 specific antibody is afucosylated.” Claim 3 recites “A method”. Examiner suggests to amend claim 11 to recite “The method of claim 3…”
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3, 5-13, and 15-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
Claim 3 recites a method of treating a tyrosinase-related protein 1 (TYRP1)-expressing cancer in an individual comprising administering to said individual a therapeutically effective amount of an anti-TYRP1/anti-CD3 bispecific antibody in combination with a second TYRP1-specific antibody, wherein the anti-TYRP1/anti-CD3 bispecific antibody comprises a first antigen binding moiety which specifically binds to TYRP1 comprising a heavy chain variable domain VH of SEQ ID NO: 1 and a light chain variable domain VL of SEQ ID NO: 2, and a second antigen binding moiety which specifically binds to CD3 comprising a heavy chain variable domain VH of SEQ ID NO: 3 and a light chain variable domain VL of SEQ ID NO: 4, and wherein the second TYRP1-specific antibody comprises an antigen binding moiety which specifically binds to TYRP1. Dependent claim 17 recites that the said immunotherapy of claim 16 comprises adoptive cell transfer, administration of monoclonal antibodies, administration of a cancer vaccine, or T-cell engaging therapies.
Thus, the rejection is directed towards the following:
the second TYRP-1 specific antibody: The claims identify the second TYRP-1 specific antibody by function only, that is to bind to TYRP-1 and treat a TYRP-1 expressing cancer, they do not recite the structure of the antibody the second TYRP-1 specific antibody.
The broad genus of “immunotherapy”, that includes adoptive cell transfer, such as CAR-T-cells, T-cell receptor modified T-cells, CAR-NK cells, monoclonal antibodies, cancer vaccines, and T-cell engaging therapies.
The instant specification discloses that the second TYRP1-specific antibody comprises a heavy chain variable domain VH of SEQ ID NO: 1 and a light chain variable domain VL of SEQ ID NO: 2. [0011, and pages 34-36] Thus, the instant specification describe a single anti- TYRP1 antibody that binds to TYRP1 and treats as claimed. The specification fails to disclose any other structural sequence required of the second TYRP1 specific antibody to possess the function of binding TYRP1 and treats TYRP1-expressing cancer.
Additionally, the instant specification fails to provide adequate written description support for the genus of “immunotherapy” that falls within the scope of the claims, and fails to provide any specific examples, other than examples of cancer vaccines as listed in paragraph 0015 of the published specification.
ANTIBODIES/ADOPTIVE CELL TRANSFER:
State of the Art:
By the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246) . 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al.,3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 2005 42–44, 60596, page 879).
The structure activity relationship of the CDR antigen binding region that recognizes TYRP1 is not known, and the binding epitopes cannot be predicted based on the antibody sequences. Patel et al (Generation and characterization of a therapeutic human antibody to melanoma antigen TYRP1. Hum Antibodies. 2007;16(3-4):127-36) and Balderes et al (US20090232823 A1) both teach that TYRP1 (tyrosinase-related protein 1) is a melanosomal membrane glycoprotein involved in melanin biosynthesis and teaches the development of a TYRP1 antibody. Patel teaches that the use of human anti-TYRP1 monoclonal antibodies for the treatment of melanoma may represent a viable therapeutic approach. [Conclusion] Thus, antibodies that target this antigen, TYRP1, are not well known in the art.
At the time of filing, antibody and/or CAR(s) antigen binding domain functionality was/were known to depend on the entire structure, particularly a full complement of six CDRs. With regards to anti-cancer antibodies, Chames et al (British J. Pharmacology, 2009, 157, 220-233) teaches that there are several challenges to development of therapeutic antibodies, including anti-cancer antibodies. Vaillant et al (Antibodies 2025, 14(2), 35) teaches the use of monoclonal antibodies in cancer therapy and teaches the vast use of antibodies and diversity of these antibodies. However, these antibodies face challenges including production, specialized administrations, etc. Thus, the genus of anti-cancer antibodies is vast, and the specification does not disclose possession of the entire genus of anti-cancer antibodies. Zhang et al (Engineering CAR-T cells. Biomark Res. 2017 Jun 24;5:22) teaches that CAR-T cells generally comprise an extracellular antigen-binding domain comprising an scFv, a spacer, a transmembrane domain, and an intracytoplasmic domain (See Figure 1). Zhang teaches that although CAR-T cells have shown promising activity, there still remains challenges and high-quality CAR-T products need to be ensured through optimization protocols. The prior art does not teach, however, a CAR without the full structure or target that would allow the CAR to bind to a specific antigen.
To provide adequate written description and evidence of possession of the claimed composition antibody genus, the instant specification can structurally describe representative antibodies, that function to recognize TYRP1 and treating functions as claimed, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for antibodies that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The TYRP1 antigen provides no information about the structure of an antibody inhibits it.
Given the lack of representative examples to support the full scope of the claimed antibodies that bind to TYRP1, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
EXAMINER SUGGESTION: Amend claim 5 to recite the limitations of claim 4.
Regarding the cancer vaccine:
It has been interpreted that a cancer vaccine comprising neoepitopes is capable of inducing an immune response in a patient, specifically inducing neoepitope-specific CD8+ T cells. The definition of vaccine in the online Merriam-Webster on-line dictionary is a preparation that is administered (as by injection) to stimulate the body's immune response against a specific infectious agent or disease.
The instant specification does not disclose any examples of any neoepitope structure or list. The instant specification discloses the following:
[0115] In some embodiments, immunotherapy comprises administering of a cancer vaccine. A skilled artisan would appreciate that a cancer vaccine exposes the immune system to a cancer-specific antigen and an adjuvant. In some embodiments, the cancer vaccine is selected from a group comprising: sipuleucel-T, GVAX, ADXS11-001, ADXS31-001, ADXS31-164, ALVAC-CEA vaccine, AC Vaccine, talimogene laherparepvec, BiovaxID, Prostvac, CDX110, CDX1307, CDX1401, CimaVax-EGF, CV9104, DNDN, NeuVax, Ae-37, GRNVAC, tarmogens, GI-4000, GI-6207, GI-6301, ImPACT Therapy, IMA901, hepcortespenlisimut-L, Stimuvax, DCVax-L, DCVax-Direct, DCVax Prostate, CBLI, Cvac, RGSH4K, SCIB1, NCT01758328, and PVX-410.
Thus, the instant specification does not provide adequate written description of the genus of cancer vaccines to be administered in the claimed invention. Although the specification discloses examples, the claims encompass all cancer vaccines discovered in the future. Furthermore, the specification does not disclose which peptides are capable of inducing an immune response.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative of antibodies, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
The specification does not provide adequate written description of the claimed invention. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the. . .claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the Applicant had possession at the time of invention of the claimed invention, the cancer vaccine.
The Federal Circuit addressed the application of the written description requirement to DNA-related inventions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). The court stated that “[a] written description of an invention involving a chemical genus, like a description of a chemical species, requires a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials.” Id. At 1567, 43 USPQ2d at 1405. The court concluded that “naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” Id.
In this case, the specification does not describe the genus of cancer vaccines of that are capable of functioning in a vaccine that satisfies either the Lilly or Enzo standards. The instant claims attempt to administer every type of RNA cancer vaccine and do not limit it to the specific type of cancer vaccine that is recited in the claims.
A search of the art demonstrates the complexity and challenges of utilizing cancer vaccines. Gracia-Grijo et al. (Frontiers in Immunology 2019 10 1-19) teaches the complications of cancer vaccines targeting neoantigens. Gracia-Grijo teaches although clinical trials testing vaccines targeting neoantigens have demonstrated they are safe and well tolerated, whether individualized immunotherapies targeting neoantigens can mediate effective antitumor responses in a broader patient population, remains an open question. Gracia-Grijo teaches that despite all the technological innovation and development of novel screening assays, the rapid and precise identification of the bona fide neoantigens in any given patient remains a major hurdle that will need to be overcome to translate the potential of neoantigen targeting into effective therapies for patients with cancer. [Conclusion, pg 14] Hu et al (Nature Reviews Immunology 2018 18, 168–182) teaches the complications of cancer vaccine production and use, including but not limited to, tumor heterogeneity between and within tumors is a major challenge to the development of cancer immunology. [pg 3, building cancer vaccines] Although the specification provides an example of one cancer vaccine, it does not provide enough support for the full scope of cancer vaccines as claimed. Thus, out of an unknown and likely very large number of structures and targets capable of being used in a vaccine, the specification only discloses one example of a cancer vaccine. The specification does not disclose sufficient examples of cancer vaccines that are capable of treating cancer.
Thus, the specification does not provide an adequate written description of the genus of cancer vaccines that is required to practice the claimed invention. The instant disclosure does not adequately describe the scope of the claimed genus of administered agents, which encompasses a substantial variety of subgenera. Since the disclosure fails to provide sufficient relevant identifying characteristics, and because the genus is highly variant, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Claims 3-13 and 15-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating tyrosinase-related protein 1 (TYRP1) expressing melanoma, does not reasonably provide enablement for treatment of all tyrosinase-related protein 1 (TYRP1) expressing cancers.. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
BREADTH OF CLAIMS: Claim 1 recites “A method of treating a tyrosinase-related protein 1 (TYRP1)-expressing cancer in an individual comprising administering to said individual a therapeutically effective amount of an anti-TYRP1/anti-CD3 bispecific antibody in combination with a second TYRP1-specific antibody, wherein the anti-TYRP1/anti-CD3 bispecific antibody comprises a first antigen binding moiety which specifically binds to TYRP1 comprising a heavy chain variable domain VH of SEQ ID NO: 1 and a light chain variable domain VL of SEQ ID NO: 2, and a second antigen binding moiety which specifically binds to CD3 comprising a heavy chain variable domain VH of SEQ ID NO: 3 and a light chain variable domain VL of SEQ ID NO: 4, and wherein the second TYRP1-specific antibody comprises an antigen binding moiety which specifically binds to TYRP1.” Dependent claim 15 recites: “The method of claim 3, wherein the cancer is breast cancer, lung cancer, colon cancer, ovarian cancer, melanoma, bladder cancer, renal cancer, kidney cancer, liver cancer, head and neck cancer, colorectal cancer, melanoma, pancreatic cancer, gastric carcinoma cancer, esophageal cancer, mesothelioma, prostate cancer, leukemia, a lymphoma, or a myeloma.”
PRESENCE OR ABSENCE OF EXAMPLES: The Examples in the specification discloses the combination of an anti-TYRP1/anti-CD3 bispecific antibody as monotherapy and in combination with an anti-TYRP1-IgG antibody in mice injected with melanoma cell lines. [Example 2] The instant specification does not disclose any other examples of other types of cancers comprising administering the instantly claimed combination.
STATE OF THE ART: With regards to tyrosinase-related protein 1 (TYRP1), Lai et al (Angewandte Chemie (International ed. in English) vol. 56,33 (2017): 9812-9815) teaches that tyrosinase enzyme is involved in the biosynthesis of melanin and that TYRP1 variants are significantly associated with the risk of melanoma. [Abstract, pg 9812 col 1-2] Spreafico et al. (“Phase 1, first-in-human study of TYRP1-TCB (RO7293583), a novel TYRP1-targeting CD3 T-cell engager, in metastatic melanoma: active drug monitoring to assess the impact of immune response on drug exposure.” Frontiers in oncology vol. 14 1346502. 21 Mar. 2024) also teaches that TYRP1 is an enzyme functionally involved in melanin synthesis that is selectively expressed in the melanocyte lineage. Spreafico teaches that TYRP1 is a tumor antigen expressed in over 60^ of cutaneous metastatic melanomas. Spreafico teaches that the bispecific antibody that targets CD3 allows for increased tumor antigen avidity and tumor cell killing because it allows for T-cell activation and concomitant T-cell mediated killing of TYRP-1 positive melanoma cells. [pg 2, 2nd column – pg 3 1st column] Hackett et al. (“TYRP1 directed CAR T cells control tumor progression in preclinical melanoma models.” Molecular therapy. Oncology vol. 32,3 200862. 22 Aug. 2024) teaches that TYRP1 is expressed on many melanomas and teaches that TYRP1 is a valid and potentially safe target for melanoma therapy. [pg 1, 2nd column – pg 2, 1st column] A search of the art does not demonstrate that the tumor antigen, TYRP1, is expressed on many other cancers as the antigen is mainly involved in melanin synthesis as the above art describes.
PREDICITABILITY: The specification lacks the critical steps necessary in presenting some type of response in a population of hosts deemed necessary to treat all types of cancers with the instantly claimed combination. The amount of experimentation required to formulate such guidance would be enormous; one would have to demonstrate the efficacy of the agent in several models across in a treatment setting. Thus, considering the high level of skill in the art, the state of the art, the level of predictability, and the guidance and examples provided, the experimentation.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine cancer is treated with the administration of the instantly claimed combination to predictably treat as claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining whether each agent treats as claimed. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim 16 -18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the individual to be treated with or pre-treated with specific immunotherapy, such as cytokines, does not reasonably provide enablement for treatment or pre-treatment with the broad genus of immunotherapy, that includes all types of adoptive cell transfer, monoclonal antibodies cancer vaccines, and T-cell engaging therapies. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
BREADTH OF CLAIMS: Claim 16 recites “The method of claim 3, wherein the individual is treated with or was pre-treated with immunotherapy.” The instant specification does not define immunotherapy, rather states in paragraph [0018] of the published specification that immunotherapy comprises “ In one aspect, the patient is treated with or was pre-treated with immunotherapy. In one aspect, said immunotherapy comprises adoptive cell transfer, administration of monoclonal antibodies, administration of cytokines, administration of a cancer vaccine, T cell engaging therapies, or any combination thereof. In one aspect, the adoptive cell transfer comprises administering chimeric antigen receptor expressing T-cells (CAR T-cells), T-cell receptor (TCR) modified T-cells, tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor (CAR)-modified natural killer cells, T cell receptor (TCR) transduced cells, or dendritic cells, or any combination thereof”.
Dependent claim 17 recites “the method according to claim 16, wherein said immunotherapy comprises adoptive cell transfer, administration of monoclonal antibodies, administration of cytokines, administration of a cancer vaccine, T-cell engaging therapies, T-cell engaging therapies, or any combination thereof.” Dependent claim 18 recites “The method according to claim 17, wherein the adoptive cell transfer comprises administering chimeric antigen receptor expressing T-cells (CAR T-cells), T-cell receptor (TCR) modified T-cells, tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor (CAR)-modified natural killer cells, T cell receptor (TCR) transduced cells, or dendritic cells, or any combination thereof.”
Thus, the claims are drawn to the broad genus of immunotherapy for the treatment TYRP-1 expressing cancer.
PRESENCE OR ABSENCE OF EXAMPLES: The instant specification does not disclose any examples of pre-treatment or treatment with any of the immunotherapies that are recited in the claims. The Examples in the specification discloses the combination of an anti-TYRP1/anti-CD3 bispecific antibody as monotherapy and in combination with an anti-TYRP1-IgG antibody. The mice in the in vivo experiment were not pre-treated or treated with any immunotherapy. [Example 2]
STATE OF THE ART: The art demonstrates the challenges of combining any agents for treatment of cancer. It is well known that the art of anti-cancer therapy is highly unpredictable, for example, Gura (Science, 1997, 278:1041-1042) teaches that researchers face the problem of sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile and teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models that only 29 have actually been shown to be useful for chemotherapy See p. 1041, see 1st and 2nd para. Furthermore, Kaiser (Science, 2006, 313: 1370) teaches that 90% of tumor drugs fail in patients. See 3rd col., 2nd to last para. Additionally, Chames et al (British J. of Pharmacology, 2009, 157, 220-233) teach that there are several challenges to development therapeutic antibodies. These challenges include functional limitations such as inadequate pharmacokinetics, tissue accessibility and impaired interactions with the immune system (Abstract). Additionally, Chames teaches several limitations of therapeutic antibodies such as affinity between the antibody and its antigen, competition with patient’s IgG, and efficiency issues in triggering the immune response (pages 224-225). Thus, the art demonstrates that agents any immunotherapy cannot be used in combination with anti-cancer agents due to the challenges of these agents.
PREDICITABILITY: The specification lacks the critical steps necessary in presenting some type of response in a population of hosts deemed necessary to treat or pre-treat with all of the broad genus of “immunotherapy” and any of the ones listed in claim 17. The amount of experimentation required to formulate such guidance would be enormous; one would have to demonstrate the efficacy of the agent in several models across several different types of agents in a treatment setting. Thus, considering the high level of skill in the art, the state of the art, the level of predictability, and the guidance and examples provided, the experimentation.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine agent is administered to which population of subjects could predictably treat as claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining whether each agent treats as claimed. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 3-12, 15 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Freimoser-Grundschober et al (WO2020127619 A1; Published 6/25/2020; cited in IDS 12/13/2024), in view of Kang et al (US20090232823 A1; Published 9/17/2009).
Freimoser-Grundschober teaches a method of treating a method of treating a tyrosinase-related protein 1 (TYRP1)-expressing cancer, melanoma, in an individual comprising administering to said individual a therapeutically effective amount of an anti-TYRP1/anti-CD3 bispecific antibody in combination with a second anti-cancer agent.
Freimoser-Grundschober teaches that the anti-TYRP1/anti-CD3 bispecific antibody comprises a first antigen binding moiety which specifically binds to TYRP1 comprising a heavy chain variable domain VH of SEQ ID NO: 18, which matches 100% to the instantly claimed SEQ ID NO: 1, and a light chain variable domain VL of SEQ ID NO: 22, which matches 100% to the instantly claimed SEQ ID NO: 2, and a second antigen binding moiety which specifically binds to CD3 comprising a heavy chain variable domain VH of SEQ ID NO: 13, which matches 100% to the instantly claimed SEQ ID NO: 3, and a light chain variable domain VL of SEQ ID NO: 14, which matches 100% to the instantly claimed SEQ ID NO: 4. Freimoser-Grundschober teaches that the bispecific antibody comprises a polypeptide sequence of SEQ ID NO: 23, which matches 100% to the instantly claimed SEQ ID NO: 5. [pg 4 lines 1-10, 29-34, pg 5 lines 1-6, pgs 34-40, pgs 99-100; pgs 103, lines 4-15, see sequence alignments below]
Regarding claim 4, Freimoser-Grundschober teaches the sequences of the antibody that binds to TYRP-1. [see sequence alignments below]
Regarding claims 5 and 6, Freimoser-Grundschober teaches the anti-TYRP1/anti-CD3 bispecific antibody is of human IgG1 or human IgG4 subclass.
Regarding claims 7-9, and 19: Freimoser-Grundschober teaches the following:
the anti-TYRP1/anti-CD3 bispecific antibody has reduced or minimal effector function, that results from an effectorless Fc mutation.
the effectorless Fc mutation is L234A/L235A or L234A/L235A/P329G or N297A or D265A/N297A
wherein the TYRP1-specific antibody comprises an Fc domain with improved effector function, improved ADCC function
[pg 3, lines 29-34, pgs 82, lines 30-34, pg 83; pg 85]
Regarding claims 11 Freimoser-Grundschober teaches the TYRP1-specific antibody is afucosylated. [pg 30] Regarding claim 15, Freimoser-Grundschober teaches that the cancer treated may be melanoma. [pg 99]
Freimoser-Grundschober demonstrates in Examples 6 and 7 that the bispecific antibody induced T cell activation and tumor cell lysis, mediated significant efficacy in terms of tumor growth inhibition compared to the vehicle group in vivo. Freimoser-Grundschober teaches that the anti-CD3/antiTYRP1 bispecific antibody may contain a third antigen that targets TYRP1. Freimoser-Grundschober also teaches that the bispecific antibody may be combined with other specific agents.
However, Freimoser-Grundschober does not explicitly teach that the third antigen that targets TYRP1 in this combination is a second TYRP-1 specific antibody and that the patient is treated with immunotherapy.
Kang teaches a method of treating melanoma comprising administering an anti-TYRP1 antibody. Kang teaches that the antibody may be combined with an anti-neoplastic agent. [0022] Kang teaches that the anti-TYRP1-specific antibody is of human IgG1 subclass. [0026] Kang teaches and demonstrates that the TYRP-1 specific antibody comprises an Fc domain with improved effector function, such as improved antibody-dependent cellular cytotoxicity (ADCC) function. [0087, 0097, 0098]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine an anti-TYRP1/anti-CD3 bispecific antibody and a second TYRP-1 specific antibody to treat a TYRP-1-expressing melanoma. One would have been motivated to, and have a reasonable expectation of success, because: (1) Freimoser-Grundschober teaches a method of treating tyrosinase-related protein 1 (TYRP1)-expressing melanoma comprising administration of the instantly claimed anti-TYRP1/anti-CD3 bispecific antibody in combination with a second anti-cancer agent, (2) Freimoser-Grundschober teaches that the anti-CD3/anti-TYRP1 bispecific antibody may contain a third antigen as part of a multispecific antibody, in which the third antigen targets TYRP-1, and (4) Kang teaches a method of treating melanoma comprising administering an anti-TYRP1 antibody and teaches that the antibody may be combined with an anti-neoplastic agent.
Those of skill in the art recognize that the two agents, a bispecific anti-TYRP1/anti-CD3 bispecific antibody and a TYRP-1 specific antibody, both known to successfully, pharmaceutically treat TYRP-1 expressing cancer in vivo, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat TYRP-1 expressing cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective at treating the same patient population, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two compositions each of which is taught by the prior art to be useful for the same purpose, to treat TYRP-1 expressing cancer.
Sequence Alignments
SEQ ID NO: 1
RESULT 1
BHY13143
(NOTE: this sequence has 9 duplicates in the database searched)
ID BHY13143 standard; protein; 121 AA.
XX
AC BHY13143;
XX
DT 20-AUG-2020 (first entry)
XX
DE Anti-TYRP1 antibody heavy chain variable region, SEQ ID 18.
XX
KW DHICA oxidase; TYRP1 protein; antibody; antibody production;
KW antibody therapy; cancer; cytostatic; heavy chain variable region;
KW therapeutic; tyrosine-related protein 1.
XX
OS Unidentified.
XX
CC PN WO2020127619-A1.
XX
CC PD 25-JUN-2020.
XX
CC PF 19-DEC-2019; 2019WO-EP086144.
XX
PR 21-DEC-2018; 2018EP-00214994.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Freimoser-Grundschober A, Hofer T, Hosse R, Moessner E;
CC PI Nicolini VG, Umana P, Waldhauer I, Richter W, Knaupp A;
CC PI Trochanowska H;
XX
DR WPI; 2020-57258Y/055.
XX
CC PT New antibody that binds to cluster of differentiation (CD)3, comprises
CC PT 1st antigen binding domain, comprising heavy and light chain variable
CC PT regions comprising complementary determining regions, used as medicament
CC PT for treating cancer.
XX
CC PS Claim 21; SEQ ID NO 18; 203pp; English.
XX
CC The present invention relates to a novel antibody specifically binding to
CC CD3, useful in preparing a medicament for treating cancer. The antibody
CC comprises a first antigen binding domain having heavy chain variable
CC region (VH) comprising CDRs of BHY13127, BHY13128 and BHY13130, and light
CC chain variable region (VL) having CDRs of BHY13133-BHY13135. The
CC invention also provides: an isolated polynucleotide encoding the antibody
CC ; a host cell comprising the isolated polynucleotide; a method for
CC producing the anti-CD3 antibody by culturing the host cell and recovering
CC the antibody; a pharmaceutical composition comprising the antibody and a
CC pharmaceutically acceptable carrier; and a method for treating a disease
CC in an individual, wherein the disease can be cancer.
XX
SQ Sequence 121 AA;
Query Match 100.0%; Score 644; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGFNIKDYFLHWVRQAPGQGLEWMGWINPDNGNTVY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGFNIKDYFLHWVRQAPGQGLEWMGWINPDNGNTVY 60
Qy 61 AQKFQGRVTMTADTSTSTVYMELSSLRSEDTAVYYCTRRDYTYEKAALDYWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRVTMTADTSTSTVYMELSSLRSEDTAVYYCTRRDYTYEKAALDYWGQGTLVTVS 120
Qy 121 S 121
|
Db 121 S 121
SEQ ID NO: 2
RESULT 1
BHY13147
(NOTE: this sequence has 9 duplicates in the database searched)
ID BHY13147 standard; protein; 107 AA.
XX
AC BHY13147;
XX
DT 20-AUG-2020 (first entry)
XX
DE Anti-TYRP1 antibody light chain variable region, SEQ ID 22.
XX
KW DHICA oxidase; TYRP1 protein; antibody; antibody production;
KW antibody therapy; cancer; cytostatic; light chain variable region;
KW therapeutic; tyrosine-related protein 1.
XX
OS Unidentified.
XX
CC PN WO2020127619-A1.
XX
CC PD 25-JUN-2020.
XX
CC PF 19-DEC-2019; 2019WO-EP086144.
XX
PR 21-DEC-2018; 2018EP-00214994.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Freimoser-Grundschober A, Hofer T, Hosse R, Moessner E;
CC PI Nicolini VG, Umana P, Waldhauer I, Richter W, Knaupp A;
CC PI Trochanowska H;
XX
DR WPI; 2020-57258Y/055.
XX
CC PT New antibody that binds to cluster of differentiation (CD)3, comprises
CC PT 1st antigen binding domain, comprising heavy and light chain variable
CC PT regions comprising complementary determining regions, used as medicament
CC PT for treating cancer.
XX
CC PS Claim 21; SEQ ID NO 22; 203pp; English.
XX
CC The present invention relates to a novel antibody specifically binding to
CC CD3, useful in preparing a medicament for treating cancer. The antibody
CC comprises a first antigen binding domain having heavy chain variable
CC region (VH) comprising CDRs of BHY13127, BHY13128 and BHY13130, and light
CC chain variable region (VL) having CDRs of BHY13133-BHY13135. The
CC invention also provides: an isolated polynucleotide encoding the antibody
CC ; a host cell comprising the isolated polynucleotide; a method for
CC producing the anti-CD3 antibody by culturing the host cell and recovering
CC the antibody; a pharmaceutical composition comprising the antibody and a
CC pharmaceutically acceptable carrier; and a method for treating a disease
CC in an individual, wherein the disease can be cancer.
XX
SQ Sequence 107 AA;
Query Match 100.0%; Score 565; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASGNIYNYLAWYQQKPGKVPKLLIYDAKTLADGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASGNIYNYLAWYQQKPGKVPKLLIYDAKTLADGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDVATYYCQHFWSLPFTFGQGTKLEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDVATYYCQHFWSLPFTFGQGTKLEIK 107
SEQ ID NO: 3
RESULT 7
BHY13138
(NOTE: this sequence has 6 duplicates in the database searched)
ID BHY13138 standard; protein; 453 AA.
XX
AC BHY13138;
XX
DT 20-AUG-2020 (first entry)
XX
DE Anti-CD3 antibody heavy chain, SEQ ID 13.
XX
KW CD3; antibody; antibody production; antibody therapy; cancer; cytostatic;
KW heavy chain; therapeutic.
XX
OS Unidentified.
XX
CC PN WO2020127619-A1.
XX
CC PD 25-JUN-2020.
XX
CC PF 19-DEC-2019; 2019WO-EP086144.
XX
PR 21-DEC-2018; 2018EP-00214994.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Freimoser-Grundschober A, Hofer T, Hosse R, Moessner E;
CC PI Nicolini VG, Umana P, Waldhauer I, Richter W, Knaupp A;
CC PI Trochanowska H;
XX
DR WPI; 2020-57258Y/055.
XX
CC PT New antibody that binds to cluster of differentiation (CD)3, comprises
CC PT 1st antigen binding domain, comprising heavy and light chain variable
CC PT regions comprising complementary determining regions, used as medicament
CC PT for treating cancer.
XX
CC PS Example 2; SEQ ID NO 13; 203pp; English.
XX
CC The present invention relates to a novel antibody specifically binding to
CC CD3, useful in preparing a medicament for treating cancer. The antibody
CC comprises a first antigen binding domain having heavy chain variable
CC region (VH) comprising CDRs of BHY13127, BHY13128 and BHY13130, and light
CC chain variable region (VL) having CDRs of BHY13133-BHY13135. The
CC invention also provides: an isolated polynucleotide encoding the antibody
CC ; a host cell comprising the isolated polynucleotide; a method for
CC producing the anti-CD3 antibody by culturing the host cell and recovering
CC the antibody; a pharmaceutical composition comprising the antibody and a
CC pharmaceutically acceptable carrier; and a method for treating a disease
CC in an individual, wherein the disease can be cancer.
XX
SQ Sequence 453 AA;
Query Match 100.0%; Score 662; Length 453;
Best Local Similarity 100.0%;
Matches 125; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFQFSSYAMNWVRQAPGKGLEWVSRIRSKYNNYAT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFQFSSYAMNWVRQAPGKGLEWVSRIRSKYNNYAT 60
Qy 61 YYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHTTFPSSYVSYYGYWGQGTL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHTTFPSSYVSYYGYWGQGTL 120
Qy 121 VTVSS 125
|||||
Db 121 VTVSS 125
SEQ ID NO: 4
RESULT 10
BHY13139
(NOTE: this sequence has 15 duplicates in the database searched)
ID BHY13139 standard; protein; 216 AA.
XX
AC BHY13139;
XX
DT 20-AUG-2020 (first entry)
XX
DE Anti-CD3 antibody light chain, SEQ ID 14.
XX
KW CD3; antibody; antibody production; antibody therapy; cancer; cytostatic;
KW light chain; therapeutic.
XX
OS Unidentified.
XX
CC PN WO2020127619-A1.
XX
CC PD 25-JUN-2020.
XX
CC PF 19-DEC-2019; 2019WO-EP086144.
XX
PR 21-DEC-2018; 2018EP-00214994.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Freimoser-Grundschober A, Hofer T, Hosse R, Moessner E;
CC PI Nicolini VG, Umana P, Waldhauer I, Richter W, Knaupp A;
CC PI Trochanowska H;
XX
DR WPI; 2020-57258Y/055.
XX
CC PT New antibody that binds to cluster of differentiation (CD)3, comprises
CC PT 1st antigen binding domain, comprising heavy and light chain variable
CC PT regions comprising complementary determining regions, used as medicament
CC PT for treating cancer.
XX
CC PS Example 2; SEQ ID NO 14; 203pp; English.
XX
CC The present invention relates to a novel antibody specifically binding to
CC CD3, useful in preparing a medicament for treating cancer. The antibody
CC comprises a first antigen binding domain having heavy chain variable
CC region (VH) comprising CDRs of BHY13127, BHY13128 and BHY13130, and light
CC chain variable region (VL) having CDRs of BHY13133-BHY13135. The
CC invention also provides: an isolated polynucleotide encoding the antibody
CC ; a host cell comprising the isolated polynucleotide; a method for
CC producing the anti-CD3 antibody by culturing the host cell and recovering
CC the antibody; a pharmaceutical composition comprising the antibody and a
CC pharmaceutically acceptable carrier; and a method for treating a disease
CC in an individual, wherein the disease can be cancer.
XX
SQ Sequence 216 AA;
Query Match 100.0%; Score 575; Length 216;
Best Local Similarity 100.0%;
Matches 109; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGGTNKRAPGT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGGTNKRAPGT 60
Qy 61 PARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVL 109
|||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVL 109
SEQ ID NO: 5
RESULT 1
BHY13148
(NOTE: this sequence has 11 duplicates in the database searched)
ID BHY13148 standard; protein; 674 AA.
XX
AC BHY13148;
XX
DT 20-AUG-2020 (first entry)
XX
DE Anti-TYRP1 VH-CH1(EE)-anti-CD3 VL-CH1Fc (knobPGLALA) construct, SEQ 23.
XX
KW CD3; DHICA oxidase; TYRP1 protein; antibody production; antibody therapy;
KW cancer; cytostatic; heavy chain; heavy chain constant region;
KW light chain variable region; multispecific antibody; mutein; therapeutic;
KW tyrosine-related protein 1.
XX
OS Homo sapiens.
OS Chimeric.
OS Synthetic.
OS Unidentified.
XX
CC PN WO2020127619-A1.
XX
CC PD 25-JUN-2020.
XX
CC PF 19-DEC-2019; 2019WO-EP086144.
XX
PR 21-DEC-2018; 2018EP-00214994.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Freimoser-Grundschober A, Hofer T, Hosse R, Moessner E;
CC PI Nicolini VG, Umana P, Waldhauer I, Richter W, Knaupp A;
CC PI Trochanowska H;
XX
DR WPI; 2020-57258Y/055.
XX
CC PT New antibody that binds to cluster of differentiation (CD)3, comprises
CC PT 1st antigen binding domain, comprising heavy and light chain variable
CC PT regions comprising complementary determining regions, used as medicament
CC PT for treating cancer.
XX
CC PS Example 4; SEQ ID NO 23; 203pp; English.
XX
CC The present invention relates to a novel antibody specifically binding to
CC CD3, useful in preparing a medicament for treating cancer. The antibody
CC comprises a first antigen binding domain having heavy chain variable
CC region (VH) comprising CDRs of BHY13127, BHY13128 and BHY13130, and light
CC chain variable region (VL) having CDRs of BHY13133-BHY13135. The
CC invention also provides: an isolated polynucleotide encoding the antibody
CC ; a host cell comprising the isolated polynucleotide; a method for
CC producing the anti-CD3 antibody by culturing the host cell and recovering
CC the antibody; a pharmaceutical composition comprising the antibody and a
CC pharmaceutically acceptable carrier; and a method for treating a disease
CC in an individual, wherein the disease can be cancer.
XX
SQ Sequence 674 AA;
Query Match 100.0%; Score 3589; Length 674;
Best Local Similarity 100.0%;
Matches 674; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGFNIKDYFLHWVRQAPGQGLEWMGWINPDNGNTVY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGFNIKDYFLHWVRQAPGQGLEWMGWINPDNGNTVY 60
Qy 61 AQKFQGRVTMTADTSTSTVYMELSSLRSEDTAVYYCTRRDYTYEKAALDYWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRVTMTADTSTSTVYMELSSLRSEDTAVYYCTRRDYTYEKAALDYWGQGTLVTVS 120
Qy 121 SASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
Qy 181 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDGGGGSGGGGSQAVVT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDGGGGSGGGGSQAVVT 240
Qy 241 QEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGGTNKRAPGTPARFS 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGGTNKRAPGTPARFS 300
Qy 301 GSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVLSSASTKGPSVFPLAPS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVLSSASTKGPSVFPLAPS 360
Qy 361 SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 420
Qy 421 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 480
Qy 481 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 540
Qy 541 DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKG 600
Qy 601 FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA 660
Qy 661 LHNHYTQKSLSLSP 674
||||||||||||||
Db 661 LHNHYTQKSLSLSP 674
Claim(s) 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Freimoser-Grundschober et al (WO2020127619 A1; Published 6/25/2020; cited in IDS 12/13/2024) and Kang et al (US20090232823 A1; Published 9/17/2009). as applied to claims 3-12, 15 and 19 above, and further in view of Nichola et al (“Immunomodulatory cytokines as therapeutic agents for melanoma.” Immunotherapy vol. 3,5 (2011): 673-90).
The teachings of Freimoser-Grundschober and Kang are described above. However, they do not teach that the individual treated is further treated with immunotherapy, such as cytokines.
Nichola teaches melanoma is the most aggressive form of skin cancer and treatment options are limited. [pg 1, malignant melanoma]. Nichola teaches the use of cytokines for the treatment of melanoma. For example, Nichola teaches that IFN-α can act directly upon melanoma cells to inhibit cellular growth, angiogenesis and promote apoptosis. [pg 3, 3rd paragraph] Nichola further teaches that it would be of particular interest to combine melanoma-specific peptides and agents that target Tregs with IL-2, IL-15 or IL-18, and that evidence supports synergy between cytokine immunotherapy and other therapeutic approaches in melanoma. [Abstract, pg 11, conclusion]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine immunotherapy, such as cytokines, with the instantly claimed combination, for the treatment of tyrosinase-related protein-1 expressing melanoma. One would have been motivated to, and have a reasonable expectation of success because: (1) Freimoser-Grundschober teaches a method of treating a method of treating a tyrosinase-related protein 1 (TYRP1)-expressing melanoma comprising administration of the instantly claimed anti-TYRP1/anti-CD3 bispecific antibody in combination with a second anti-cancer agent, (2) Kang teaches a method of treating melanoma comprising administering an anti-TYRP1 antibody and teaches that the antibody may be combined with an anti-neoplastic agent, (3) Nichola teaches methods of treating melanoma comprising administering cytokines as immunotherapy, and teaches evidence supports synergy between cytokine immunotherapy and other therapeutic approaches in melanoma.
Given the recognized need to treat TYRP-1 expressing melanoma, given the known methods of treating melanoma comprising administering a bispecific anti-TYRP1/CD3 bispecific antibody and an anti-TYRP1 antibody, as well as the role of cytokine immunotherapy, one of skill in the art could have pursued administering cytokine immunotherapy in combination with the anti-TRYP1/CD3 bispecific antibody and the anti-TYRP1 antibody, with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3-10, 15, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,672,858 in view of Kang et al (US20090232823 A1; Published 9/17/2009).
The U.S. Patent recites a method of treating a TYRP-1-expressing cancer in a human individual having a TYRP-1-expressing cancer, the method comprising administering to the individual an effective amount of a bispecific antibody molecule, wherein the bispecific antibody molecule comprises: (a) a first antigen-binding domain that binds to human CD3 and (b) a second antigen-binding domain that binds to human TYRP-1. The U.S. Patent recites that the first and second antigen binding domain comprise sequences that match 100% to the instantly claimed sequences. The U.S. Patent also recites that the bispecific antibody molecule further comprises a third antigen-binding domain that binds to TYRP-1, which matches 100% to the instantly claimed sequences of the second antibody that binds to TYRP-1. The referenced U.S. Patent and the instant application are claiming common subject matter, as follows:
Instant Application: 18/668,810
U.S. Patent: 11,672,858
A method of treating a tyrosinase-related protein 1 (TYRP1)-expressing cancer in an individual comprising administering to said individual a therapeutically effective amount of an anti-TYRP1/anti-CD3 bispecific antibody in combination with a second TYRP1-specific antibody, wherein the anti-TYRP1/anti-CD3 bispecific antibody comprises a first antigen binding moiety which specifically binds to TYRP1 comprising a heavy chain variable domain VH of SEQ ID NO: 1 and a light chain variable domain VL of SEQ ID NO: 2, and a second antigen binding moiety which specifically binds to CD3 comprising a heavy chain variable domain VH of SEQ ID NO: 3 and a light chain variable domain VL of SEQ ID NO: 4, and wherein the second TYRP1-specific antibody comprises an antigen binding moiety which specifically binds to TYRP1.
4. The method according to claim 3, wherein the second antibody comprises a heavy chain variable domain VH of SEQ ID NO: 1 and a light chain variable domain VL of SEQ ID NO: 2.
2. The method of claim 1, wherein (a) the first antigen-binding domain comprises a VH that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7 and a VL that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11, and/or (b) the second antigen-binding domain comprises a VH that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18 and a VL that is at least 95% identical to the amino acid sequence of SEQ ID NO: 22.
6. The method of claim 4, wherein the bispecific antibody molecule further comprises a third antigen-binding domain that binds to TYRP-1, and wherein the second antigen-binding domain and the third antigen-binding domain each comprises (a) a VH comprising a HCDR 1 comprising the amino acid sequence DYFLH (SEQ ID NO: 15), a HCDR 2 comprising the amino acid sequence WINPDNGNTVYAQKFQG (SEQ ID NO: 16), and a HCDR 3 comprising the amino acid sequence RDYTYEKAALDY (SEQ ID NO: 17), and (b) a VL comprising a LCDR 1 comprising the amino acid sequence RASGNIYNYLA (SEQ ID NO: 19), a LCDR 2 comprising the amino acid sequence DAKTLAD (SEQ ID NO: 20), and a LCDR 3 comprising the amino acid sequence QHFWSLPFT (SEQ ID NO: 21).
5. The method according to claim 3, wherein the anti-TYRP1/anti-CD3 bispecific antibody is of human IgG1 or human IgG4 subclass.
6. The method of claim 5, wherein the TYRP1-specific antibody is of human IgG1 subclass.
7. The method of claim 3, wherein the anti-TYRP1/anti-CD3 bispecific antibody has reduced or minimal effector function.
8. The method of claim 7, wherein the minimal effector function results from an effectorless Fc mutation.
13. The method of claim 4, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor and/or effector function.
14. The method of claim 4, wherein the Fc domain is a human Fc domain and/or an IgG Fc domain.
15. The method of claim 3, wherein the cancer is breast cancer, lung cancer, colon cancer, ovarian cancer, melanoma, bladder cancer, renal cancer, kidney cancer, liver cancer, head and neck cancer, colorectal cancer, melanoma, pancreatic cancer, gastric carcinoma cancer, esophageal cancer, mesothelioma, prostate cancer, leukemia, a lymphoma, or a myeloma.
15. The method of claim 1, wherein the TYRP-1-expressing cancer is a skin cancer.
16. The method of claim 15, wherein the skin cancer is melanoma.
The U.S. Patent does not recite that the method comprises a second TYRP-1 specific antibody.
Kang teaches a method of treating cancer comprising administering an anti-TYRP1 antibody. Kang teaches that the antibody may be combined with an anti-neoplastic agent. [0022] Kang teaches that the anti-TYRP1-specific antibody is of human IgG1 subclass. [0026] Kang teaches and demonstrates that the TYRP-1 specific antibody comprises an Fc domain with improved effector function, such as improved antibody-dependent cellular cytotoxicity (ADCC) function. [0087, 0097, 0098]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine an anti-TYRP1/anti-CD3 bispecific antibody and a second TYRP-1 specific antibody to treat a TYRP-1-expressing cancer. One would have been motivated to, and have a reasonable expectation of success, because: (1) the U.S. Patent recites a method of treating a method of treating a tyrosinase-related protein 1 (TYRP1)-expressing cancer comprising administration of the instantly claimed anti-TYRP1/anti-CD3 bispecific antibody in combination with a second anti-cancer agent, (2) the U.S. Patent that the anti-CD3/anti-TYRP1 bispecific antibody may contain a third antigen as part of a multispecific antibody, in which the third antigen targets TYRP-1, and (4) Kang teaches a method of treating cancer comprising administering an anti-TYRP1 antibody and teaches that the antibody may be combined with an anti-neoplastic agent.
Those of skill in the art recognize that the two agents, a bispecific anti-TYRP1/anti-CD3 bispecific antibody and a TYRP-1 specific antibody, both known to successfully, pharmaceutically treat TYRP-1 expressing cancer in vivo, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat TYRP-1 expressing cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective at treating the same patient population, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two compositions each of which is taught by the prior art to be useful for the same purpose, to treat TYRP-1 expressing cancer.
Claims 16 and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,672,858 and Kang et al (US20090232823 A1; Published 9/17/2009) as applied to claims 3-10, 15, and 19, and further in view of Nichola et al (“Immunomodulatory cytokines as therapeutic agents for melanoma.” Immunotherapy vol. 3,5 (2011): 673-90).
The U.S. Patent and Kang do not disclose the individual treated is further treated with immunotherapy, such as cytokines.
Nichola teaches melanoma is the most aggressive form of skin cancer and treatment options are limited. [pg 1, malignant melanoma]. Nichola teaches the use of cytokines for the treatment of melanoma. For example, Nichola teaches that IFN-α can act directly upon melanoma cells to inhibit cellular growth, angiogenesis and promote apoptosis. [pg 3, 3rd paragraph] Nichola further teaches that it would be of particular interest to combine melanoma-specific peptides and agents that target Tregs with IL-2, IL-15 or IL-18, and that evidence supports synergy between cytokine immunotherapy and other therapeutic approaches in melanoma. [Abstract, pg 11, conclusion]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine immunotherapy, such as cytokines, with the instantly claimed combination, for the treatment of tyrosinase-related protein-1 expressing melanoma. One would have been motivated to, and have a reasonable expectation of success because: (1) The U.S. Patent a method of treating a method of treating a tyrosinase-related protein 1 (TYRP1)-expressing melanoma comprising administration of the instantly claimed anti-TYRP1/anti-CD3 bispecific antibody in combination with a second anti-cancer agent, (2) Kang teaches a method of treating melanoma comprising administering an anti-TYRP1 antibody and teaches that the antibody may be combined with an anti-neoplastic agent, (3) Nichola teaches methods of treating melanoma comprising administering cytokines as immunotherapy, and teaches evidence supports synergy between cytokine immunotherapy and other therapeutic approaches in melanoma.
Given the recognized need to treat TYRP-1 expressing melanoma, given the known methods of treating melanoma comprising administering a bispecific anti-TYRP1/CD3 bispecific antibody and an anti-TYRP1 antibody, as well as the role of cytokine immunotherapy, one of skill in the art could have pursued administering cytokine immunotherapy in combination with the anti-TRYP1/CD3 bispecific antibody and the anti-TYRP1 antibody, with a reasonable expectation of success.
Conclusion
Conclusion: Claims 3-13 and 15-19 are rejected.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
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