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 .
The Amendments filed December 6, 2024 and February 24, 2025 in response to the Office Actions of September 6, 2024 and February 20, 2025 are acknowledged and have been entered.
Status of the Claims
Claims 1-118, 125, 127, and 128 are canceled. Claims 119-124, 126, and 129-136 are pending and currently being examined.
Withdrawn Claim Rejections
Claim objections of claims 127, 131, and 126 are withdrawn in view of amendment.
Claim rejection of claims 125 and 135 under 35 U.S.C. 112(b) is withdrawn in view of amendment.
Claim rejection of claims 121-124 under 35 U.S.C 112(d) is withdrawn in view of amendment.
New Rejections (necessitated by amendments)
Claim Interpretation
For the purposes of examination, claim 119 is interpreted to be drawn to a modified immune cell expressing an antigen-targeting domain in an extracellular domain. The instant specification does not define what an extracellular domain is.
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.
This is a New Ground of Rejection necessitated by the amendment. Claims 119-124, 126, and 129-136 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 119 recites a modified immune cell that recognizes a target antigen, comprising in its genome: a nucleic acid sequence encoding an antigen recognition moiety for the target antigen, wherein the antigen recognition moiety comprises an antibody fragment and is the nucleic acid sequence encoding the antigen recognition moiety is inserted in an endogenous cell surface receptor gene to form a modified cell surface receptor gene, wherein the endogenous cell surface receptor gene comprises an extracellular domain- coding sequence and the insertion is an in-frame insertion at a specific site within the extracellular domain-coding sequence in the endogenous cell surface receptor gene such that the antigen recognition moiety is operably linked to or inserted within the extracellular domain-coding sequence of the endogenous cell surface receptor,wherein the target antigen is a cell surface protein.
The structure of the modified immune cell is unclear. While the antigen recognition moiety is inserted in an endogenous cell surface rector gene, how this gene relates to the immune cell is unclear. For example, what is the structures on the surface of the immune cell? As such, the metes and bounds of the claims are ambiguous.
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 119-124, 126, and 129-136 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 claims contain 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 for the reasons of record.
Claims 119-124, 126, and 129-136 are directed to a modified immune cell that recognizes a target antigen, comprising in its genome: a nucleic acid sequence encoding an antigen recognition moiety derived from an antibody molecule for the target antigen inserted in an endogenous cell surface receptor gene to form a modified cell surface receptor gene, wherein the target antigen is selected from TAG-72, CD19, CD20, CD47, folate receptor alpha (Fra), or BCMA.
The specification teaches anti-TAG-72/CD3 CRISPR FP T cells mediate potent cell killing of TAG-72hi expressing target cells (Figs. 10A and 10B). The specification also teaches anti-CD19/CD3 CRISPR FP T cells mediate potent cell killing of CD19+ target tumor cells (Figure 11). However, the specification does not offer support for CD20, CD47, folate receptor alpha (Fra), or BCMA as target antigens.
For a claim to a genus, a generic statement that defines a genus of substances
by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members.
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
Applicants have only demonstrated possession of two representative examples of target antigens listed in the instant claims as target antigens of the modified immune cell. The two disclosed species of target antigens used in the instant specification is not sufficient to predict the structures of the full scope of target antigens encompassed by the instant claims. Since it is clear that additional experimentation is required to identify the full scope of modified immune cells wherein the target antigens are selected from those recited in the claims, it is concluded that Applicants were not in possession of the full scope of the instant claims at the effective filing date of the instant application.
Thus, there is a lack of written description regarding the target antigens selected for the modified immune cell.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir.2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).See also MPEP 2163.04.
Response to Arguments for Rejections under U.S.C. 112(a):
Applicant's arguments filed June 13, 2025 have been fully considered but they are not persuasive.
Applicant argues that the instant specification discloses actual reduction to practice examples of both TAG-72 and CD19 scFvs to illustrate the modified immune cells and shows that the modified immune cells work for its intended purpose, in Examples 2, 3, and 5-8 of the specification as-filed. Applicant further argues that Examples 1,3, 4, and 8-10 of the instant specification as-filed further discloses processes of making the modified immune cells. Applicant argues that the specific target antigen is not central to the claims, rather the structural modification of the endogenous receptor is what defines the claimed invention.
Applicant states:
“[w]hen analyzing each claim as a whole, it is evident that the claims are directed to a modified immune cell comprising a modification in an endogenous receptor to give the endogenous receptor a specificity that is separated from its normal mode of action. Applicant submits that the specific target antigen is not central to the claims and that the structural modification defines the claimed invention. As such, the specification describes the claimed invention demonstrating that the inventors were in possession of the claimed invention on the filing date. The specification describes the CRISPR-based insertion methods, the precise genomic location within the receptor's coding region, and the use of the cell's own regulatory elements to drive expression. The specification exemplifies the claimed invention using two distinct types of antigens: one a carbohydrate antigen expressed by tumor cells, and the other a protein marker expressed by B lymphocytes. These examples illustrate that the approach is broadly applicable across antigens. A person of ordinary skill in the art would understand that the modified endogenous receptor of the claimed modified immune cell is widely applicable across a range of antigens”. As such, applicant asserts that the instant specification provides adequate written description support for the amended claims.
This is not found persuasive for following reasons:
Applicant provides two species of working examples in the instant specification. However, two species in the specification is not sufficient to support possession of the entire genus. Adequate written description 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.” Regents of the University of California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997).
Additionally, Applicant’s argument that the specification discloses CRISPR-based insertion methods, is not persuasive because the written description requirement is separate and distinct from the enablement requirement. See MPEP 2161.
However, although the claims have been amended, claim 119 is drawn to modified immune cell, a broad limitation that encompasses a very vast list of possibilities. As stated above in the rejection, there is insufficient evidence for the claimed recitation and there is not a representative number of species to adequately describe the claimed genus.
Claim Rejections - 35 USC § 102
This is a New Ground of Rejection necessitated by applicant’s amendment to the claims. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 119-124, 129 and 133 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by “Chimeric antigen receptor-modified T cells: CD19 and the road beyond,” Salter et al, (Blood 2018, 131;24:2621-2629).
Regarding claim 119, Salter teaches modifying T cells by transferring genes encoding synthetic chimeric antigen receptors (CARs) that redirect specificity to a cell-surface molecule in a non-MHC-restricted fashion (Introduction). Salter teaches gene editing to generate a modified CAR cell and teaches different designs for the CAR in Figure 1. Salter discloses a scFv linked to an extracellular domain CD28 and linked to modified signals,
Regarding claims 120-121, Salter teaches modifying one or two signals in a TCR and costimulatory molecule expression on T cells (Figure 1).
Regarding claim 122, Salter teaches the endogenous cell surface receptor on the modified immune cell can be CD28 (Figure 1).
Regarding claim 123, Salter teaches the endogenous cell surface receptor can be CD3epsilon, CD3gamma, or CD3delta (Figure 1).
Regarding claim 124, Salter teaches the TCR can be TCR alpha or TCR beta (Figure 1).
Regarding claim 129, Salter teaches the target antigen on the modified CAR T cell is CD19 and teaches successfully using this approach to target CD19 (page 2622, paragraph 1, Figure 1).
Regarding claim 133, Salter teaches the antigen recognition moiety for the targeted antigen is a scFv (page 2621).
Therefore, the reference teachings anticipate the instant invention.
Claims 119, 121-124, 126, 129-130, and 132-133 rejected under 35 U.S.C. 102(a)(1) as being anticipated by “Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection,” Eyquem et al, (Nature 2017, 543: 113-118).
Regarding claim 119, Eyquem teaches using CRISPR/Cas9 genome editing to place a CD19-specific 1928z CAR under the transcriptional control of TRAC-CAR. Eyquem teaches designing a guide RNA targeting the first exon of TRAC and an AAV vector repair matrix encoding a self-cleaving P2A peptide followed by the CAR cDNA (page 113, second column, Figure 1A).
Regarding claim 121, Eyquem teaches electroporating T cells to insert the guide RNA designed (page 113).
Regarding claim 122, Eyquem teaches designing the CAR which comprises an scFv, preceded by a CD8a leader peptide, followed by a CD28 hinge-transmembrane-intracellular regions and CD3ζ intracellular domain (page 118, first column).
Regarding claims 123 and 124, Eyquem teaches staining of the CD3 complex to assess cell surface expression and demonstrates that CD3 is a functional marker of TCRalpha expression.
Regarding claim 126, Eyquem teaches the 1928z-pA CAR sequence inserted in frame at the ATG (page 118, first column).
Regarding claims 129-130, and 132, Eyquem teaches the inserted CAR is a CD19-specific (Abstact).
Regarding claim 133, Eyquem teaches the CAR comprises a scFV region (page 118).
Therefore, the reference teachings anticipate the instant invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 119 and 120 is rejected under 35 U.S.C. 103 as being unpatentable over “Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection,” Eyquem et al, (Nature 2017, 543: 113-118) in view of “Chimeric antigen receptor-modified T cells: CD19 and the road beyond,” Salter et al, (Blood 2018, 131;24:2621-2629).
Regarding claim 119, Eyquem teaches using CRISPR/Cas9 genome editing to place a CD19-specific 1928z CAR under the transcriptional control of TRAC-CAR. Eyquem teaches designing a guide RNA targeting the first exon of TRAC and an AAV vector repair matrix encoding a self-cleaving P2A peptide followed by the CAR cDNA (page 113, second column, Figure 1A).
Eyquem does not teach the modified immune cell wherein the modified immune cell comprises two or more modified cell surface receptor genes and recognizes two or more different target antigens. Salter remedies this deficiency.
Salter teaches modifying T cells by transferring genes encoding synthetic chimeric antigen receptors (CARs) that redirect specificity to a cell-surface molecule in a non-MHC-restricted fashion (Introduction). Salter teaches gene editing to generate a modified CAR cell and teaches different designs for the CAR in Figure 1. Salter discloses a scFv linked to an extracellular domain CD28 and linked to modified signals.
Regarding claims 120, Salter teaches modifying one or two signals in a TCR and costimulatory molecule expression on T cells (Figure 1). Salter also teaches that targeting multiple molecules simultaneously might increase the frequency of patients achieving durable remissions without adding toxicity (page 2624, second column).
It would have been prima facie obvious to a person of ordinary skill in the art to modify an immune cell as recited in the instant claim, wherein the modified immune cell comprises two or more modified cell surface receptor genes and recognizes two or more different target antigens.
One would have been motivated to and have a reasonable expectation of success given Eyquem teaches successfully modifying a T cell by inserting a CAR, and Salter also teaches modifying a T cell with a CAR with two signals on the immune cell, in order to increase the frequency of remissions in patients. One would have been motivated to target two antigens instead of one as that would provide more effective therapy and potential benefits to patients, as opposed to targeting only one antigen.
Claims 119, 131, 134, and 136 are rejected under 35 U.S.C. 103 as being unpatentable over “Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection,” Eyquem et al, (Nature 2017, 543: 113-118) in view of Jacoby et al (WO 2019/089610).
Regarding claim 119, Eyquem teaches using CRISPR/Cas9 genome editing to place a CD19-specific 1928z CAR under the transcriptional control of TRAC-CAR. Eyquem teaches designing a guide RNA targeting the first exon of TRAC and an AAV vector repair matrix encoding a self-cleaving P2A peptide followed by the CAR cDNA (page 113, second column, Figure 1A).
Eyquem does not teach the modified immune cell wherein the target antigen is a viral protein expressed on the surface of virally-infected cells. Eyquem also does not teach wherein the nucleic acid sequence inserted encodes the antigen recognition moiety and a linker. Eyquem does not teach the modified immune cell is differentiated from a modified stem cell comprising the modified cell surface receptor gene. Jacoby remedies these deficiencies.
Regarding Claim 131, Jacoby teaches engineering of the endogenous TCR loci by integrating the variable regions of a TCR of interest. The introduced TCR may bind to antigens such as tumor antigens or viral antigens [00301].
Regarding Claims 134 and 136, Jacoby teaches the engineering of the endogenous TCR loci by integrating the variable regions of a TCR of interest. A construct comprising a TCR-b chain separated from a TCR-alpha variable region by a self-cleaving linker sequence is integrated into the endogenous TRAC locus (Figure 5A). Jacoby also teaches that the modified cell may be a T cell, an NK cell or a stem cell capable of differentiating into an immune cell [00105-00109].
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to combine the teachings of Eyquem with those of Jacoby to make a modified immune cell wherein the target antigen is a viral protein expressed on the surface of virally-infected cells, wherein the modified immune cell encodes the antigen recognition moiety and a linker, and an immune cell capable of differentiating from a stem cell. A person of ordinary skill in the art would recognize that these claim elements are known in the art and one of skill in the art could have combined these elements by known methods.
One of ordinary skill in the art would have been motivated to and would have had a reasonable expectation of success given: Eyquem teaches modifying an immune cell by inserting a CAR into the TRAC locus and Jacoby teaches the immune cell may bind to viral proteins. Jacoby also provides motivation for integrating a linker into the TRAC locus.
Claims 119 and 135 are rejected under 35 U.S.C. 103 as being unpatentable over “Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection,” Eyquem et al, (Nature 2017, 543: 113-118) in view of “HIV-specific humoral immune responses by CRISPR/Cas9-edited B cells,” Hartweger et al, (J Exp Med 2019 Jun 3; 216(6):1301-1310).
Regarding claim 119, Eyquem teaches using CRISPR/Cas9 genome editing to place a CD19-specific 1928z CAR under the transcriptional control of TRAC-CAR. Eyquem teaches designing a guide RNA targeting the first exon of TRAC and an AAV vector repair matrix encoding a self-cleaving P2A peptide followed by the CAR cDNA (page 113, second column, Figure 1A).
Eyquem does not teach the modified immune cell with a nucleic acid sequence inserted, wherein the nucleic acid sequence encoding the antigen recognition moiety is less than 1.5 kb in length. Hartweger remedies this deficiency.
Regarding claim 135, Hartweger discloses modifying B cells using CRISPR/Cas9 to insert an exogenous sequence encoding a HIV-specific antibody into the genome at the endogenous IgH locus (abstract); a full-length light chain and the variable region of a heavy chain are inserted (insert region size: 1420bp) into the IgH gene after the endogenous variable regions so that they are under the control of the IgH promoter (Figure S3D).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to combine the teachings of Eyquem with those of Hartweger to make a modified immune cell wherein the nucleic acid sequence insert is less than 1.5 kb.
One of ordinary skill in the art would have been motivated to and would have had a reasonable expectation of success given Eyquem teaches modifying an immune cell by inserting a nucleic acid sequence and Hartweger teaches limiting the nucleic acid insert size to less than 1.5 kb. It is well known in the art that a small nucleic acid insert can be conducive to more efficient transfer of genes and a higher editing efficiency.
All other objections and rejections recited in the Office Action mailed December 17, 2024 are hereby withdrawn in view of amendments.
Conclusion: Claims 119-124, 126, and 129-136 are rejected.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NADA AHMED MAHMOUD ELMANSY whose telephone number is (571)270-0810. The examiner can normally be reached Monday-Friday 9am-5pm EST.
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/NADA AHMED MAHMOU ELMANSY/Examiner, Art Unit 1646
/CHUN W DAHLE/Primary Examiner, Art Unit 1641