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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 4, 2025 has been entered.
Claim Rejections - 35 USC § 112 – Necessitated by Amendment
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, 4, 115, and 116 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.
Claims 3 and 115 recite “said HLA gene” is line 5. Said HLA gene is referenced earlier in claims 3 and 115 in reference to both the first and second cells. It is unclear to which HLA gene (i.e. of the first cell or of the second cell) “said HLA gene” of line 5 refers? For the purpose of compact prosecution, said HLA gene of line 5 is interpreted as referring to that of the second cell.
Claims 4 and 116 are rejected for depending from claims 3 and 115 and failing to remedy the indefiniteness.
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
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.
Claims 1, 6, 109-111, 113, 114, and 117-123 are rejected under 35 U.S.C. 103 as being unpatentable over Fedorov et al. (US 2015/0376296 A1; Published: December 31, 2015) in view of Natali et al. (PNAS. 86: 6719-6723: Published: September 1989), and Mehta et al. (Frontiers in Immunology. 9: 283; Published: February 15, 2018), and as evidenced by Human Cytokine Magnetic 10-Plex Panel Product Information Sheet (Invitrogen; Published: June 30, 2017).
Regarding claims 1 and 114, US 2015/0376296 A1 teaches selecting the iCAR target antigen; see paragraphs 0119 and 0122. US 2015/0376296 A1 teaches HLAs as a potential target guiding the selection by stating “[u]niversally expressed immunogenic antigens that are down regulated by tumors but not normal tissues, such as human leukocyte antigens (HLAs).” Regarding the intracellular domain from an inhibitory receptor in claims 1 and 114, US 2015/0376296 A1 teaches several, including PD-1 and CTLA-4; see paragraphs 0124-0144. Regarding building an iCAR in claims 1 and 114, US 2015/0376296 A1 teaches designing the iCAR where the intracellular domain from an inhibitory receptor replaces the CD28/CD3ζ domain of the typical CAR and retaining the CD8 transmembrane and hinge domains; see paragraphs 0200-0201. Regarding claim 114, US 2015/0376296 A1 teaches that 2BA-L isoform is a negative immune regulator for NK cells; see paragraph 0137.
Regarding selecting an aCAR known to induce activation of the effector T cell in claims 1 and 114, US 2015/0376296 A1 teaches using “19-28z” which is “an extensively characterized second-generation CAR currently used in clinical trials [which] provides activation and CD28 costimulation in response to the CD19 antigen”; see paragraph 0222. Regarding expressing the iCAR and aCAR in claim 1, US 2015/0376296 A1 teaches a dual expressing T cell; see paragraph 0227.
To assess whether the iCAR can inhibit the aCAR signal in claims 1 and 114, US 2015/0376296 A1 teaches coculturing anti-CD19 aCAR- and anti-PSMA iCAR-expressing cells with CD19+ AAPCs and CD19+ and PSMA+ off-target cells and measuring the killing of the CD19+ AAPCs by fluorescence microscopy; see paragraphs 0217, 0222, and 0223.
Note that in claims 1 and 114, the limitation “and wherein said first cell and said second cell both express said target surface protein” appears within step (ii)(b) which is recited in the alterative with step (ii)(a). Thus, the claims are interpreted as not requiring that the first and second cells both express the target surface protein of the aCAR when a known aCAR is used as in step (ii)(a).
Regarding the step of identifying a pair in claims 1 and 114, US 2015/0376296 A1 teaches that the anti-CD19 aCAR- and anti-PSMA iCAR pair reduced off-target by 91%; see paragraph 0223.
Regarding the cell type used to express the CAR in claims 1 and 114, US 2015/0376296 A1 teaches using T cells and NK cells for tumor antigen specific CARs; see paragraph 0146.
Regarding claims 109, 110, 118, and 119, US 2015/0376296 A1 teaches using the iCAR- and aCAR-expressing immune cells to treat a subject with neoplasia/cancer wherein the neoplasia/cancer express the aCAR target antigen and, in certain embodiments, the cancer is breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, lymphoma, leukemia, or lung cancer; see paragraph 0011. In paragraph 0061, US 2015/0376296 A1 teaches that neoplasia includes colorectal cancer.
Regarding claims 113 and 121, US 2015/0376296 A1 teaches quantifying cytokines secretion using Luminex assays (Invitrogen); see paragraph 0208. The Human Cytokine Magnetic 10-Plex Panel Product Information Sheet (Invitrogen) evidences that Luminex technology utilizes magnetic beads to quantify cytokine secretion and, therefore, the Luminex assay used in US 2015/0376296 A1 is a CBA assay.
Similarly, regarding claims 111 and 120, US 2015/0376296 A1 teaches incubating T cells expressing either only the aCAR or both the iCAR and aCAR with target and off-target cells each engineered to express a different fluorescent probe and using time-lapsed microscopy to assess the cell death of each the target or off-target cell; see paragraph 0227. US 2015/0376296 A1 teaches that the T cell expressing both the iCAR and aCAR resulted in cell death of the target cells and sparing of the off-target cells, thus, identifying an iCAR and aCAR pair that attenuates cell death of the first cell type (i.e. off-target cells) while inducing the cell death of the second cell type (i.e. the target cells).
US 2015/0376296 A1 does not teach an antigen binding domain specific for an extracellular polymorphic epitope from an HLA gene nor does it teach the HLA genes recited in claims 6 and 117.
Finally, the reference does not directly mention activating intracellular domains appropriate for use in NK cells.
Regarding the HLA specific antigen binding domain of claims 1, 6, 114, and 117, Natali et al. teaches an antigen binding domain called BB7.2 which recognizes a polymorphic HLA-A2 epitope; see Abstract.
Neither US 2015/0376296 A1 nor Natali et al. teach CAR activating intracellular domains for NK cells.
Regarding the aCAR known to induce activation of an NK cell in claim 114, Mehta et al. teaches that NK cells expressing an anti-CD19 CAR with CD28/CD3ζ domains had superior cytotoxicity against CD19 positive cells; see page 4. Because Mehta et al. teaches that CD28/CD3ζ activation domains were successful in NK cells expressing a CAR and US 2015/0376296 A1 teaches that the dual CAR expressing cells can be NK cells, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to use the known ”19-28z” CAR taught in US 2015/0376296 A1 expressed in NK cells.
Given that Natali et al. teaches the antigen binding domain BB7.2 binds the polymorphic HLA-A2 epitope and that HLA-A2 expression is not detectable or reduced in several cancers (i.e. BB7.2 does not bind to several cancer cells, including colorectal cancer) and that US 2015/0376296 A1 teaches that HLA proteins would be appropriate targets for the iCAR, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success and predictability to use the anti-HLA-A2 antigen binding domain in place of the anti-CD19 antigen binding domain exemplified in US 2015/0376296 A1. One would be motivated to make this modification because 70-80% of endometrial, colorectal, mammary, and renal tumors; 40-60% of soft-tissue, skin, ovary, urinary bladder, prostate, and stomach tumors; and 25-30% of melanomas and lung carcinomas tested demonstrated not detectable or reduced expression of the HLA-A2 epitope using the BB7.2 antibody.
Note that the limitations of claims 122 and 123 are only required when screening an antigen binding library is utilized – which is optional – not when selecting a known antigen binding domain.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 3, 4, 115, and 116 are rejected under 35 U.S.C. 103 as being unpatentable over Fedorov et al. (US 2015/0376296 A1; Published: December 31, 2015) in view of Natali et al. (PNAS. 86: 6719-6723: Published: September 1989), and Mehta et al. (Frontiers in Immunology. 9: 283; Published: February 15, 2018), and as evidenced by the Human Cytokine Magnetic 10-Plex Panel Product Information Sheet (Invitrogen; Published: June 30, 2017) as applied to claim(s) 1, 3, 6, 109-111, 113-115, and 117-123 above, and further in view of Chang et al. (The Journal of Immunology. 174(3): 1462-1471; Published: February 15, 2008).
The teachings of US 2015/0376296 A1 in view of Natali et al., and Mehta et al., and as evidenced by the Human Cytokine Magnetic 10-Plex Panel Product Information Sheet as related to claim(s) 1, 3, 6, 109-111, 113-115, and 117-123, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither US 2015/0376296 A1, Natali et al., nor Mehta et al. teach the loss of the HLA-A2 epitope as a result of at least one substitution, deletion, or insertion in the HLA gene or a SNP.
Chang et al. teaches the loss of the HLA-A2 antigen as the result of a single cytosine deletion, i.e. a SNP, in the HLA-A2 gene exon 4; see Abstract for example.
Given that Chang et al. teaches that a single deletion, i.e. a SNP, in the HLA-A2 exon 4 can result in the loss of HLA-A2 antigen expression in melanoma cells, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to select an aCAR + iCAR pair as taught by US 2015/0376296 A1, wherein the iCAR comprises an anti-HLA-A2 antibody as taught by Natali et al. which cannot bind the second cell, a cancer cell, as the result of a SNP.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Response to Arguments
Applicant’s amendments filed June 3, 2026 are acknowledged. Any rejection not repeated above is resolved by amendment.
Applicant argues that Fedorov et al. only teaches an iCAR targeting down-regulated HLA molecules, that neither Fedorov et al. nor Natali et al. teach two different allelic variants: one present on the first cell and one present on the second cell, and that there’s no motivation for using the antibody taught by Natali et al. in the iCAR of Fedorov et al.
Applicant appears suggests that down-regulation of HLA in cancer as taught in Fedorov et al. is synonymous with reduced expression or the loss of expression of HLA and does not encompass scenarios where tumor cells and normal cells may express different allelic variants of the same HLA gene. Applicants’ interpretation of how the skilled artisan would have interpreted the down-regulation of HLA in cancer is directly contradicted by Campoli et al. (Vaccine. 20: A40-A45; Published: December 19, 2002), who demonstrates that years before the disclosure of Fedorov et al., the art understood that down-regulation of HLA encompasses the loss of one haplotype; see Figure 2 for example. In such instances, the tumor cells, having lost only one haplotype, would express the allospecificities of the second haplotype. Further, Campoli et al. teaches that down regulation “by loss of the gene(s) encoding the lost HLA class I heavy chain(s) or by mutations which inhibit their transcription or translation […] the mutations found in HLA class I heavy chains range from large deletions to single base deletions”. Indeed, these alternations of the HLA class I heavy chain could encompass one or both alleles resulting in different HLA-A variants.
Natali et al. teaches the loss of the polymorphic HLA-A2 epitope, but not the framework HLA-A, B, C determinant in several tumor samples. Indeed, loss of the HLA-A2 heavy chain epitope, but not the framework determinant region could occur by either of the HLA downregulation mechanisms highlighted from Campoli et al.: 1. Loss of the haplotype comprising the HLA-A2 allele or 2. Mutation of the HLA-A2 heavy chain. Moreover, it is noted that the instant claims do not comprise a step of identifying which HLA allelic variants are present on or expressed by the first and second cells.
Finally, Fedorov et al. teaches making immune cells comprising an aCAR targeting a tumor antigen and an iCAR, which selectively reduces or eliminates the immune activity, thereby reducing off-targ effects; see paragraph 0008 for example. Fedorov et al. teaches treating cancer with this aCAR + iCAR expressing cell and that the iCAR may target an HLA; see claims 40 and 44 for example. Natali et al. teaches and antibody which binds an HLA-A2 epitope and demonstrates that there are tumor cells which lose the HLA-A2 epitope; see page 6719. Indeed, there is a clear motivation to select the antibody of Natali et al. for use in the aCAR + iCAR expressing immune cell taught by Fedorov et al. as a potential therapeutic for cancers lacking the expression of the HLA-A2 epitope.
The rejection under 35 U.S.C. 103 is maintained.
Conclusion
No claims are allowed.
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.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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