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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 1 and 114 are objected to because of the following informalities:
In steps (ii)(b):
“APP” should be “AFP”
“EGPR” should be “EGFR”
“EGPRvIII” should be “EGFRvIII”
“PAP” should be “FAP”
“PHSR” should be “FHSR”
“GPI00” should be “GP100”
“TGP” should be “TGF”
“VEGPR2” should be “VEGFR2”
Appropriate correction is required.
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, 4, 111, 113, 115, 116, 120, and 121 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 111, 113, 120, and 121 recites the limitation "detecting activation" in line 1. There is insufficient antecedent basis for this limitation in the claim. There is not step of detecting activation in the preceding claims. Step (iv) involves “measuring activation” and is a suggested remedy.
Claim 121 recites the limitation "T cell activation marker" in line 5. There is insufficient antecedent basis for this limitation in the claim. There is not step of detecting activation in the preceding claims. Step (iv) involves “measuring activation” and is a suggested remedy. There is no T cell recited in the previous claims. It is unclear to which T cell claim 121 refers. For the purpose of compact prosecution, the claim is interpreted as reciting the “NK cell activation marker”.
Claims 3 and 115 recite two scenarios: 1. The HLA gene is located in a chromosomal region that exhibits LOH in said second cell type, or 2. The HLA gene is located in a chromosomal region that exhibits complete loss of expression of all genes in the region. Both of these scenarios should arise as the result of a substitution, deletion or insertion. In paragraph 0056 LOH is defined as “loss of chromosomal materials such as a complete chromosome or a part thereof, in one copy of the two chromosomes in a somatic cell.” First, given the LOH definition, it is unclear how the first and second scenarios differ? Second, the claim recites “a substitution, deletion or insertion” (singular) does this encompass instances where more than one nucleotide is mutated? Does this encompass more than one mutation event? Additionally, “all genes” is scenario two is a relative term. The number of genes considered to be all is relative to the chromosomal region lost.
Claims 4 and 116 recite that LOH is the result of a SNP, or single nucleotide polymorphism. A SNP is a mutation or deletion of a single base pair. It is unclear how the mutation of a single base pair because of a (singular) SNP would result in LOH as defined in the Specification as the loss of chromosomal material, either the complete or partial loss of a chromosome.
For the purpose of compact prosecution, claims 3 and 115 are interpreted as LOH of the HLA gene or loss of expression of the HLA gene, wherein either is due to one or more mutations. Support for this interpretation is found in paragraph 00628. . And claims 4 and 116 are interpreted as using SNP analysis to determine that LOH has occurred. Support for this interpretation is found beginning at paragraph 00547 on page 213.
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.
Claims 1, 3, 6, 109-111, 113-115, 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), Mehta et al. (Frontiers in Immunology. 9: 283; Published: February 15, 2018), and Maleno et al. (Immunogenetics. 56: 244-253; Published: July 16, 2004), 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.
While Natali et al. teaches the “loss” of the HLA-A2 polymorphic epitope, the paper does not state that the loss was LOH of the HLA gene nor that it was assessed by SNP analysis. Additionally, US 2015/0376296 A1 does not teach that the HLA gene is located in a chromosomal region that exhibits LOH, nor that the LOH is assessed by SNP analysis.
Maleno et al. teaches that loss of heterozygosity in chromosome region 6p21 in samples with colorectal cancer resulted in HLA-A2 haplotype deletion and loss of expression; see page 247.
Neither Natali et al. nor Maleno 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), that Maleno et al. teaches that LOH of chromosome region 6p21 results in loss of expression of HLA-A2 in some 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. Further, one would have been motivated to do so because Maleno et al. further teaches that LOH of chromosome region 6p21 results in lack of expression of HLA-A2 in some colorectal cancer cases – instances in which the resulting iCAR- and aCAR-expressing T cell or NK cell may be used therapeutically.
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 4 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), Mehta et al. (Frontiers in Immunology. 9: 283; Published: February 15, 2018), and Maleno et al. (Immunogenetics. 56: 244-253; Published: July 16, 2004). 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 Daw et al. (BMC Genetics. 6(Suppl 1): S32; Published: December 30, 2005).
The teachings of US 2015/0376296 A1 in view of Natali et al., Mehta et al., and Maleno 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., Mehta et al., nor Maleno et al., teach assessing LOH by SNP analysis. Maleno et al. which teaches LOH resulting in the loss of HLA-A2 assesses LOH by microsatellite analysis, does not teach SNP analysis.
Daw et al. teaches that “First, individual microsatellites tend to be more polymorphic, and thus more informative, than individual SNPs. Consequently, it is easier to detect genotyping errors in microsatellites and fewer microsatellite markers provide can provide the same information. Second, SNPs are far more common than microsatellites, which means that a SNP map can be far denser and potentially more informative than a microsatellite map.”; see Background. Daw et al. compares microsatellite and SNP data and concludes that the localizations of SNP data are better.
Given that given that Daw et al. teaches that SNP analysis can offer a more dense and potentially more informative SNP map compared to a microsatellite map, it would have been obvious to one of ordinary skill in the art that the LOH reported by Maleno et al. could also be assessed by SNP analysis with a reasonable expectation of success. Further, one of ordinary skill in the art may be motivated to use SNP analysis to generate a more dense and more informative genetic data map.
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 November 4, 2025 are acknowledged. Any rejection not repeated above is resolved by amendment.
Regarding the rejections under 35 U.S.C. 112(a) for failure to comply with the written description and enablement requirements, Examiner agrees with Applicant that there is adequate description of 1. Antigen binding domains which bind HLA proteins, 2. Activating CARs or Antigen binding domains which bind the tumor antigens recited in claims 1 and 114, 3. Intracellular domains from a T cell or NK cell inhibitory receptor, and 4. Intracellular domains from a T cell or NK cell activating signal transduction element in the prior art which would enable one to perform the method as presently recited in the claims without more than reasonable experimentation. The written description and enablement rejections are withdrawn.
Applicant asserts that none of the references taught an inhibitory CAR against a polymorphic epitope pf HLA. Fedorov et al. and U.S. 11,267,901, which is related to US 2015/0376296 A1 now of record, teaches targeting HLA proteins with the iCAR. And Natali et al. teaches an antigen bind domain which binds a polymorphic HLA-A2 epitope. It would have been obvious to one of ordinary skill in the art to combine these teachings for the reasons above.
Applicant asserts that the references were silent to the HLA expressed on the first cell and only taught that the second cell does not express the HLA polymorphic epitope. Fedorov et al. and U.S. 11,267,901, which is related to US 2015/0376296 A1, teach that the iCAR should target a protein, such as an HLA, which is only expressed on the non-target cell or first cell. Natali et al. teaches that the HLA-A2 expression is lost in tumor samples. For expression to have been lost, it would have had to have been previously present. To one of ordinary skill in the art, it is obvious that Natali et al. is describing a polymorphic HLA-A2 epitope which is present on normal cells, or the first cell, and not on tumor cells, the second cell.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 8:30am - 5:00pm MT.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682