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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-16, and species pancreatic cancer for cancer, in the reply filed on December 9, 2025 is acknowledged.
Claims 17-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 9, 2025.
Claims 1-16 are under consideration in this office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The application is the national stage entry of PCT/US2021/045305, which claims benefit to U.S. Provisional Application No. 63/065,388, filed August 10, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 7, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Claim Objections
Claims is objected to because it uses an acronym (i.e. scFv) without first defining what it represents in the claims. While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym.
Claim Rejections - 35 USC § 112(b)
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.
Claims 3, 5, and 8-11 are 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 1 recites the limitation "the IgG4 hinge region”. There is insufficient antecedent basis for this limitation in the claim.
Claims 3 and 8 recite the limitation "the complementarity determining region 1 (CDR1), CDR2, and CDR3 sequences”. There is insufficient antecedent basis for this limitation in the claim.
Claim 3 is directed to an anti-GPC1 single-domain antibody comprised of three CDRs from SEQ ID NO: 6 and claim 8 is directed to an anti-GPC1 antibody comprised of six CDRS from SEQ ID NOs: 2 and 4. Since CDRs are typically defined within the same numbering method (e.g., Kabat, Chothia, IMGT), and applicant has not indicated the numbering method used in the claim, it is unclear which specific combination of amino acid sequences will support the minimum structure necessary for antigen binding. Claims 5 and 9-11 are included in this rejection for being dependent on the rejected claim and for failing to cure the indefiniteness.
Claim Rejections - 35 USC § 112(a)
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.
Claim 1-2, 7, and 14-16 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.
Claims 1-2, 7, and 14-16 are directed to CARs comprising an antigen-bind domain that recognizes GPC1, but there is no structure for this domain set forth in these claims. As such, these CARs are directed to a very broad genus of antigen-binding domains defined only by function, i.e. binding to GPC1.
Antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three complementarity determining regions that provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see Almagro et al, Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1; instant PTO-892).
The art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. See for example Kussie (instant PTO-892), who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-azophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (see abstract).
Furthermore, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg 11).
As specificity of an antibody stems from the interaction of six CDRs, or three CDRs for single-domain antibodies, sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound.
Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of anti-GPC1 antigen-binding domains encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art, as evidenced by Edwards et al., 2003 (instant PTO-892), teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
According to the specification, the applicant has disclosed at least two species of anti-GPC1 antibodies that comprised either of specific CDRs. The specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish most of the members comprised within the genus claimed, specifically which six CDR amino acids sequences for the antibody or three CDR amino sequences for the single-domain antibody should be combined to yield an antigen-binding region that is capable of binding GPC1.
There is no way to determine if the antibodies represent the full breadth of what is claimed. The disclosure of these specific antibodies would not convey to the artisan that applicant was in possession of the full genus of all antibodies that possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only 2 species within the genus.
With the exception of specifically disclosed antibodies with specific CDRs, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 1-2, 7, and 14-16 do not meet the written description requirement.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 7, and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016208754, published December 29, 2016 (“Yaguchi”, instant PTO-892; machine translation retrieved from Patentscope on December 19, 2025, instant PTO-892) in view of Hudecek et al, published 2013 (see IDS from 2/7/2023).
The claims are directed to a chimeric antigen receptor (CAR) comprising a hinge consisting of SEQ ID NO: 7, a transmembrane domain, an intracellular co-stimulatory domain, an intracellular signaling domain, and an extracellular antigen-binding domain that binds to GPC1.
Yaguchi teaches a CAR comprising, from N-terminus to Ci-terminus, an extracellular domain that binds to GPC-1, a transmembrane domain, and at least one intracellular domain [0015] as in instant claim 1. The extracellular domain that binds to GPC-1 comprises the antigen binding domain of an antibody, as in instant claim 2 [0016]. The domain that binds to GPC-1 can be a scFv [0016], as in instant claim 7. The transmembrane domain can be CD28 [0019], as required by instant claim 14. A secondary stimulatory molecule is 4-1BB, as required by instant claim 15. The intracellular domain is CD3 zeta ([0022],[0026]), as required by instant claim 16.
The CAR of Yaguchi has a spacer domain between the extracellular domain and the transmembrane domain [0021], as in the hinge of instant claim 1. Yaguchi does not teach a hinge consisting of the IgG4 hinge region of SEQ ID NO: 7, as required by claim 1.
Hudecek et al teaches teach CARs directed to ROR, wherein the CAR has a short 12 amino acid IgG4 hinge with a S108P substitution, which is identical to the hinge of SEQ ID NO: 7 of instant claim 1 (pg 3154, column 2; pg 3155, column 2). Hudecek compared ROR1-CARs with different IgG4-Fc spacer domains of different lengths and found that short hinge-only extracellular spacer conferred superior lysis of ROR1-positive tumor cells and induction of T-cell effector functions compared with CARs with long spacers of Hinge-CH2-CH3 (Abstract).
Given that Yaguchi teaches a CAR comprising the claimed GPC1 binding domain, a spacer, a transmembrane domain, and an intracellular domain and further given that Hudecek teaches the claimed spacer, it would have been obvious to one of ordinary skill in the art to use the hinge of Hudecek et al in the CAR of Yaguchi. This is because there were a finite number of identified and predictable solutions for the spacer at the time the application was filed (i.e. Hinge-CH2-CH3, Hinge-CH3, or Hinge-only) (Hudecek, pg 3154, column 2). For example, Hudecek teaches that hinge regions of different lengths have different effects on the cytotoxic function of CAR-T cells (Figure 1). One would use the spacer of Hudecek in the CAR of Yaguchi and have a reasonable expectation of success, because Hudecek has demonstrated that customizing spacer design and increasing affinity of CARs enhances T-cell effector function and recognition of tumors by the CAR (abstract). The additional steps of determining spacer length are via methods described in the art (see all of Hudecek). See MPEP 2143.02.II: The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.
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 1-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,122,843 in view of Hudecek et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter: a CAR comprising the same antigen-binding domain that recognizes GPC1.
Claims 1 and 13-14 of patent ‘843 teach a CAR comprising an anti-GPC1 monoclonal antibody comprised of VH with CDR1-3 of SEQ ID NO: 2 and VL with CDR1-3 of SEQ ID NO: 4 of single-domain antibody comprised of CDR1-3 of SEQ ID NO: 6, as in the CAR of instant claims 1-13 (same SEQ ID NOs). Claim 15 of ‘843 teaches a anti-GPC1 CAR comprised of a CD28 transmembrane domain, a 4-1BB signaling moiety, and a CD3 zeta signaling domain, as in instant claims 14-16.
‘843 does not teach a hinge region as set forth in SEQ ID NO: 7, as required by claim 1.
Hudecek et al teaches CARs directed to ROR, wherein the CAR has a short 12 amino acid IgG4 hinge with a S108P substitution, which is identical to the hinge of SEQ ID NO: 7 of instant claim 1. Hudecek compared ROR1-CARs with different IgG4-Fc spacer domains of different lengths and found that short hinge-only extracellular spacer conferred superior lysis of ROR1-positive tumor cells and induction of T-cell effector functions compared with CARs with long spacers of Hinge-CH2-CH3 (Abstract).
Given that ‘843 teaches a CAR comprising the claimed GPC1 binding domain, a spacer, a transmembrane domain, and an intracellular domain and further given that Hudecek teaches the claimed spacer, it would have been obvious to one of ordinary skill in the art to use the hinge of Hudecek et al in the CAR of ‘843. This is because there were a finite number of identified and predictable solutions for the spacer at the time the application was filed. For example, Hudecek teaches that hinge regions of different lengths have different effects on the cytotoxic function of CAR-T cells (Figure 1). One would use the spacer of Hudecek in the CAR of ‘843 and have a reasonable expectation of success, because Hudecek has demonstrated that customizing spacer design and increasing affinity of CARs enhances T-cell effector function and recognition of tumors by the CAR (abstract). The additional steps of determining spacer length are via methods described in the art (see all of Hudecek). See MPEP 2143.02.II: The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.
Conclusion
No claim is allowed.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675