DETAILED ACTION
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 .
1. Claims 1-16 are currently pending and under examination in this office action.
Priority
2. Application claims priority from PCT/CN2022/111866 filed on 8/11/2022 which claims priority from foreign application CN202110925203.1 filed on 8/12/2021. No certified copy or English translation of the foreign application has been received, therefore, priority is granted to PCT/CN2022/1111866 and the effective filing date of 8/11/2022.
Claim Objections
3. Applicant is advised that should claim 9 be found allowable, claim 16 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
4. Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 8 provides for the use of the chimeric antigen receptor of claim 1 for the preparation of a medicament or a formulation for the prevention and/or treatment of a cancer or a tumor, but, since the claim does not set forth any steps involved in the method/process, it is unclear what method/process applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced.
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.
5. Claims 1-16 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.
The claims are drawn to a bispecific CAR comprising two scFv antigen-binding domains where one antigen-binding scFv is targeting HER2 and one antigen-binding scFv is targeting MESO with no amino acid sequence structure.
Thus, the claims identify the bispecific CAR by the function of binding to both HER2 and MESO with no sequence structure. Thus, the claims encompass a vast genus of bispecific CARs with two antigen-binding domains required to bind HER2 and MESO and no identified sequence structure. (See pgs. 14-18 of the instant specification).
The instant specification discloses the amino acid and nucleic acid structure of one bispecific CAR that binds to HER2 and MESO. The instant specification discloses one scFv comprising a VH region and a VL region that binds HER2 as SEQ ID NO:12 and one scFv comprising a VH and a VL region that binds MESO as SEQ ID NO:13.
Thus, the instant specification identifies one structurally distinct bispecific CAR with one structurally distinct scFv domain binding HER2 and one structurally distinct scFv domain binding MESO. The specification fails to disclose any other antigen-binding domain variants that function to bind HER2 or MESO.
To provide adequate written description and evidence of possession of the claimed bispecific CAR genus, the instant specification can structurally describe representative scFvs that function to bind HER2 and MESO, 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 preparing that product.
In this case, the only factor present in the claims is a recitation of the antigen-binding function, “targeting HER2” and “targeting MESO”. The instant specification fails to describe structural features common to the members of the antigen-binding domain that binds HER2 and MESO genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative antigen-binding domain sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antigen-binding domain does, rather than what it is. Other than for the scFvs disclosed on pages 14-18, the specification fails to provide VH and VL amino acid sequence structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antigen-binding domain sequences for the genus of CAR that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed bispecific CAR.
The claims broadly encompass any sequence variant that functions to bind HER2 and MESO. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the VH or VL regions that can be altered and still maintain HER2 and MESO binding function. Given the well-known high level of polymorphism of antigen-binding amino acid sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of bispecific CARs encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single bispecific CAR to the structure of any variants required to bind HER2 and MESO as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for scFvs that bind HER2 or MESO and 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 HER2 and MESO antigen provides no information about the structure of an antigen-binding domain that binds to it.
Given the lack of representative examples to support the full scope of the claimed scFvs required to make the bispecific CARs, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the VH and VL regions that provide HER2 and MESO-binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of bispecific CARs that function to bind HER2 and MESO that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending claim 1 to recite and require the antigen-binding domain targeting HER2 comprises SEQ ID NO:12 and the antigen-binding domain targeting MESO comprises SEQ ID NOs:13.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
6. Claim 8 is rejected under 35 U.S.C. 101 because the claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ 678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
7. Claims 1-7 and 10-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pogson (WO2019/126724 A1, pub. 6/27/2019).
Regarding claims 1-2, Pogson discloses a CAR comprising the structure of an optional signal peptide, an scFv that binds a first antigen- which could be either HER2 or MESO, an antigen-binding fragment that binds a second antigen- which could be HER2 or MESO, optionally a hinge region, a transmembrane domain, one or more co-stimulatory signaling domains and a primary signaling domain- which could be CD3ζ. (See Pogson, pgs. 2-5). Further, Pogson discloses a flexible linker between antigen-binding domains. (See Pogson, pg. 25).
Regarding claim 3, Pogson discloses that a scFv antibody fragment can be in either the VH-VL or VL-VH orientation (See Pogson, pg. 23) and include a linker between the variable regions (See Pogson, pg. 25).
Regarding claims 4-6 and 11-12 Pogson further discloses the CAR can be encoded by a polynucleotide sequence expressed through a vector in a host cell. (See Pogson, pgs. 5-6).
Regarding claims 7 and 13-15 Pogson further discloses a formulation comprising a pharmaceutically acceptable carrier and a CAR, a polynucleotide, a vector, and/or a host cell. (See Pogson, pg. 6).
Regarding claim 10, Pogson discloses a method for making the engineered immune cell by providing an immune cell to be engineered and transducing the cell through a nucleic acid molecule or a vector encoding the CAR. (See Pogson, pg. 7).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
8. Claims 1-7 and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Pogson (WO2019/126724 A1, pub. 6/27/2019) in further view of Yu (J Hem & Oncol., 2017, 10:78).
Pogson discloses a CAR comprising the structure of an optional signal peptide, an scFv that binds a first antigen- which could be either HER2 or MESO, an antigen-binding fragment that binds a second antigen- which could be HER2 or MESO, optionally a hinge region, a transmembrane domain, one or more co-stimulatory signaling domains and a primary signaling domain- which could be CD3ζ. (See Pogson, pgs. 2-5). Further, Pogson discloses a flexible linker between antigen-binding domains. (See Pogson, pg. 25).
Pogson discloses that a scFv antibody fragment can be in either the VH-VL or VL-VH orientation (See Pogson, pg. 23) and include a linker between the variable regions (See Pogson, pg. 25).
Pogson discloses the CAR can be encoded by a polynucleotide sequence expressed through a vector in a host cell. (See Pogson, pgs. 5-6).
Pogson discloses a formulation comprising a pharmaceutically acceptable carrier and a CAR, a polynucleotide, a vector, and/or a host cell. (See Pogson, pg. 6).
Pogson discloses a method for making the engineered immune cell by providing an immune cell to be engineered and transducing the cell through a nucleic acid molecule or a vector encoding the CAR. (See Pogson, pg. 7).
Pogson does not teach specifically selecting HER2 and MESO for the antigen-binding domains of the bispecific CAR.
Yu teaches that HER2 and MESO are promising targets for CAR-T cell development since they are both commonly expressed tumor associated antigens on solid tumors, have been developed by multiple research institutes, and have both received promising outcomes. (See Yu, pg. 2, column 1, paragraph 1). Yu teaches that HER2 CAR-T cells have achieved success at targeting non-breast HER2+ cancer cells that have been able to avoid anti-HER2 antibodies, including a HER2/IL-13Rα2 and a HER2/CD3 bispecific CAR-T cell. (See Yu, pgs. 5, 7 “HER2”). Yu teaches MESO is an attractive target for immune based cancer therapies and have had multiple CAR-T cells developed showing pre-clinical success at achieving anti-tumor effects. (See Yu, pgs. 8-9 “Mesothelin”). Yu also teaches that both HER2 and MESO are overexpressed on ovarian cancer cells. (See Yu, pg. 5 “HER2” paragraph 1, line 6; also pg. 8 “Mesothelin” paragraph 1, lines 8-9).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to use the bispecific CAR disclosed in Pogson with the teachings of Yu to produce the HER2-MESO bispecific CAR of the present claimed invention. It would have been obvious because Yu teaches that both HER2 and MESO are targeted antigens for treating solid tumors, including ovarian cancer, and both have been the focus of targeted antigens in CAR-T cell therapy. It would have had a reasonable expectation of success because both antigens have already had successful CAR-T cells developed that target their expression on cancer cells with HER2 having been included in bispecific CAR-T cells with success. Therefore, a person of ordinary skill in the art prior to the effective filing date would have been motivated to use the bispecific CAR of Pogson with the teachings of Yu to produce the HER2-MESO bispecific CAR as claimed.
9. Claims 9 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Pogson (WO2019/126724 A1, pub. 6/27/2019), as applied to claims 1-7 and 10-15 above, in further view of Zhang (CN112778427A pub. 5/11/2021; cited in IDS 2/12/2024).
Pogson discloses the limitations of claims 1 and 4 as discussed above.
Pogson does not disclose a kit for preparing a host cell comprising a container, and the nucleic acid molecule of claim 4 in the container.
Zhang does disclose a kit for preparing host cells comprising a container, a nucleic acid molecule for a bispecific CAR in the container.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to combine the disclosed bispecific CAR of Pogson with the kit taught in Zhang. It would have been obvious because the nucleic acid molecule is capable of being expressed in various forms and one of ordinary skill would have known to provide the nucleic acid molecule in a kit would allow a reasonable expectation of success at using the nucleic acid molecule as a commercial product. Therefore, it would have been obvious to a person of ordinary skill in the art to include the nucleic acid molecule as disclosed in Pogson in a kit similar to Zhang with a reasonable expectation of success at producing it as a commercial product.
10. Claims 1-7 and 9-16 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (CN112778427A pub. 5/11/2021; cited in IDS 2/12/2024) in further view of Yu (J Hem & Oncol., 2017, 10:78).
Zhang discloses a bispecific CAR cell targeting two different antigens having the structure of: L-scFv1-I-scFv2-H-TM-C-CD3ζ, wherein each "-" is independently a linker peptide or peptide bond; L is an optional signal peptide sequence; I is a flexible linker; H is an optional hinge region; TM is a transmembrane domain; C is co-stimulatory signaling molecule; CD3ζ is a cytoplasmic signaling sequence derived from CD3ζ, and scFv1 and scFv2 are directed to two different antigen-binding domains. (See pgs. 4-5 [0007]-[0016]).
Zhang further discloses the two antigen-binding scFvs can be arranged as either VH-VL or VL-VH, where the VH is a heavy chain variable region and VL is a light chain variable region with a linker between the variable regions. (See Zhang pgs. 5-6 [0019]-[0027]).
Zhang discloses the bispecific CAR can be encoded in a nucleic acid molecule, either isolated or included in a vector. A host cell can then be introduced to either the vector or a chromosome that has incorporated the exogenous nucleic acid of the bispecific CAR for expression of the bispecific CAR in the host cell. (See Zhang, pgs. 8-9 [0047]-[0056]).
Zhang discloses the bispecific CAR, the nucleic acid molecule encoding the CAR, the vector, or the host cell can be included in a formulation along with a pharmaceutically acceptable carrier, diluent, or excipient. (See Zhang, pg. 10 [0065]).
Zhang discloses a kit can be provided including a container and the nucleic acid molecule encoding the bispecific CAR in the container. (See Zhang, pg. 11 [0077]).
Zhang discloses a method for preparing engineered immune cells expressing the bispecific CAR of (a) providing an immune cell to be engineered; and (b) transducing a nucleic acid molecule or a vector encoding the bispecific CAR into the immune cells, thereby obtaining engineered immune cells. (See Zhang, pgs. 11-12 [0078]-[0080]).
Zhang does not disclose the scFv antigen-binding domains targeting HER2 and MESO.
Yu teaches that HER2 and MESO are promising targets for CAR-T cell development since they are both commonly expressed tumor associated antigens on solid tumors, have been developed by multiple research institutes, and have both received promising outcomes. (See Yu, pg. 2, column 1, paragraph 1). Yu teaches that HER2 CAR-T cells have achieved success at targeting non-breast HER2+ cancer cells that have been able to avoid anti-HER2 antibodies, including a HER2/IL-13Rα2 and a HER2/CD3 bispecific CAR-T cell. (See Yu, pgs. 5, 7 “HER2”). Yu teaches MESO is an attractive target for immune based cancer therapies and have had multiple CAR-T cells developed showing pre-clinical success at achieving anti-tumor effects. (See Yu, pgs. 8-9 “Mesothelin”). Yu also teaches that both HER2 and MESO are overexpressed on ovarian cancer cells. (See Yu, pg. 5 “HER2” paragraph 1, line 6; also pg. 8 “Mesothelin” paragraph 1, lines 8-9).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to use the disclosed bispecific CAR cell structure of Zhang with the teachings of Yu for making a HER2-MESO bispecific CAR with a reasonable expectation of success. It would have been obvious because Yu teaches that both HER2 and MESO are targeted antigens for treating solid tumors, including ovarian cancer, and both have been the focus of targeted antigens in CAR-T cell therapy. It would have had a reasonable expectation of success because both antigens have already had successful CAR-T cells developed that target their expression on cancer cells with HER2 having been included in bispecific CAR-T cells with success. Therefore, it would have been obvious to a person of ordinary skill in the art to use HER2 and MESO antigen-binding targets in the structure of Zhang prior to the effective filing date to produce the bispecific CAR of the present claimed invention.
Conclusion
11. Claims 1-16 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LINDSAY DUNN whose telephone number is (571)272-5825. The examiner can normally be reached Monday-Friday 8-4:30.
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/LINDSAY DUNN/Examiner, Art Unit 1644
/Laura B Goddard/Primary Examiner, Art Unit 1642
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