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 .
Detailed Action
This action is in response to the papers filed September 11, 2025.
Election/Restrictions
Applicant’s reply filed 09/11/2025 to the Requirement of Requirement/Election mailed 04/11/2025 is acknowledged.
Applicant elected without traverse:
the invention of Group 1, drawn to a modified cell, a population of cell comprising thereof, and a pharmaceutical composition comprising thereof;
a cell lacking endogenous expression of CD3;
a cell possessing endogenous expression of NKp30, NKp44, NKp46 and CD158b;
a cell having an exogenous nucleic expression construct encoding a CD16 protein;
a cell exhibiting a loss of function of TGFβR2 and CISH;
a NK cell, as the cell-type; and
breast cancer, as the disease or cancer-type.
Claim Amendments
Applicant’s amendment to the claims filed 09/11/2025 is acknowledged.
Claims 3-10, 13-14, 17-21, 24, 27-29, 32-42, 47-49, 52-79, 81-88 have been cancelled.
Claims 1-2, 11-12, 15-16, 22-23, 25-26, 30-31, 43-46, 50-51, and 80 are pending and under examination.
Priority
The instant application 17/430,382 was filed on 08/12/2021. This application is a national stage of international application PCT/US2020/018443 filed 02/14/2020, claiming priority based on U.S. Provisional Patent Applications 62/943,649, filed 12/04/2019, 62/841,684, filed 05/01/2019, 62/841,066 filed 04/30/2019, and 62/806,457 filed 02/15/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/20/2021, 05/12/2022, and 02/13/2025 have been considered.
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, or by applicant in an information disclosure statement (IDS), they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See paragraphs 350 and 360. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate action is required.
Claim Objections
Claim 23 is objected to because of the following informalities:
In claim 23, the phrase “(KKH) SaCas9, AsCpf1 (AsCas12a), LbCpf1, (LbCas12a)” should be “KKH SaCas9, AsCpf1, AsCas12a, LbCpf1, LbCas12a” to remove unnecessary parentheses. One of ordinary skill in the art would have recognized that Cpf1 and Cas12a are the same nuclease.
In claim 23, the phrase “VRQR, VRER” should be “SpCas9 VRQR variant, SpCas9 VRER variant” to provide the complete names of the nucleases.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 15-16 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.
Claim 15 recites a pluripotent or multipotent stem cell that comprises exogenous nucleic acid constructs encoding NKp30, NKp44, NKp46, and CD158b. This limitation is new matter. The specification describes a cell possessing endogenous expression of a natural cytotoxicity receptor, wherein the natural cytotoxicity receptor is NKp30, NKp44, NKp46, and/or CD158b. See, e.g., paragraphs 46-47 of the specification. However, the specification does not describe a pluripotent or multipotent stem cell that comprising exogenous nucleic acid constructs encoding NKp30, NKp44, NKp46, and CD158b, as instantly claimed. For these reasons, claim 15 includes new matter.
Dependent claim 16 is included in the basis of the rejection because it does not correct the deficiencies of the claim upon which it depends.
Claims 2, 31, 45-46, 50-51, and 80 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 2 and 45 recite the NK cell comprises a rearranged endogenous T-cell receptor (TCR), and claims 31 and 46 recites the NK cell comprises a rearranged endogenous TCR locus, wherein the rearranged TCR comprises TCRα VJ and/or TCRβ V(D)J section rearrangements and complete V-domain exons.
An adequate written description of a NK cell having a rearranged TCR locus requires more than a mere statement that it is part of the invention. What is required is either (1) a description of a common core structure shared among the members (species) of the functionally described genus or (2) a disclosure of a representative number of species of the functionally described genus. It is not sufficient to define a NK cell solely by its desired biological property, i.e., possessing a rearranged TCR locus, because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any NK cell that is capable of possessing a rearranged TCR locus. Also, naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. Thus, claiming a NK cell having a rearranged TCR locus without defining what means will do, or without disclosing a representative number of species, is not in compliance with the written description requirement.
Lanier et al. (2007) “Back to the future–defining NK cells and T cells” European journal of immunology, 37(6), 1424-1426, discloses that NK cells do not rearrange the TCR locus, by definition. Rather, TCR rearrangement is a feature of T cells, which must be distinguished from NK cells. See pages 1424-1426.
Accordingly, prior to the effective filing date of the instantly claimed invention, claiming NK cells that possess a rearranged TCR locus, as in this case, would have lacked technical sense to one of ordinary skill in the art. Applicant’s specification is not found to sufficiently describe a NK cell possessing a rearranged TCR locus, or how such a NK cell would be obtained.
Therefore, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the claimed NK cell having a rearranged TCR locus, as claimed in claims 2, 31, 45-46, 50-51, and 80, at the time the application was filed.
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.
Claim 23 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 23 contains the trademark/trade name “Sniper-Cas9” (U.S. Registration No. 5,807,670). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an engineered Cas9 variant and, accordingly, the identification/description is indefinite.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 45-46, 50-51, and 80 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.
The limitation “the modified lymphocyte” in claim 45 lacks antecedent basis.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims 46, 50-51, and 80 are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claims 45-46, 50-51, and 80 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 45 recites a series of elements (“a”, “b”, “c”), but it is unclear whether the series of elements are recited in the alternative (“or” statement) or in combination (“and” statement). Essentially, the scope of claim 45 is indefinite because there is a missing conjunction (“or”, “and”, “and/or” statement) joining the series of elements.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims 46, 50-51, and 80 are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claim 46 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 46 recites a series of elements (“a”, “b”, “c”), but it is unclear whether the series of elements are recited in the alternative (“or” statement) or in combination (“and” statement). Essentially, the scope of claim 46 is indefinite because there is a missing conjunction (“or”, “and”, “and/or” statement) joining the series of elements.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 44 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 44, dependent upon claim 43, recites a pharmaceutical composition comprising “the population of NK cells of claim 43.” However, claim 43 is not directed to a population of NK cells, but rather the claim recites “[a] population of cells comprising the modified NK cell of claim 1.” Under the broadest reasonable interpretation, claim 43 reads on a population of cells where at least one cell in the population is a NK cell and the remaining cells in the population may be another cell type, e.g., T cells. Accordingly, claim 44 does not include all the limitations of claim 43 because claim 44 only requires the (sub)population of NK cells in the population of cells of claim 43, which is a cell population that may comprise other cell types, e.g., T cells. For these reasons, claim 44 is improper dependent for failing to include all the limitations of claim 43, upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 30 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2022/0031749 A1 to Basar et al.
US 2022/0031749 A1 to Basar et al. claims priority to 11/28/2018 based on U.S. Provisional Application No. 62/772,406. The teachings relied upon in this rejection find written support in the priority document.
Regarding claim 30, Basar teaches natural killer (NK) cells possessing loss-of-function of CISH and TGFβRII, thereby increasing their functionality and enhancing their antitumor cytotoxicity. See paragraphs 6, 10, 15, 32, 35, 119, 279-284; see also paragraphs 4, 8, 13, 113, 235-240 of the priority document for written support.
Accordingly, Basar anticipates claim 30.
Claims 30 and 80 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2018/0273903 A1 to Zhang et al.
Regarding claim 30, Zhang teaches modified NK cells comprising an exogenous nucleic acid expression construct encoding a CD16 protein. The CD16 protein is a modified CD16 protein resistant to ADAM17 cleavage and having higher affinity for IgG than wildtype CD16. See, e.g., paragraphs 2, 11, 96.
Accordingly, Zhang anticipates claim 30.
Regarding claim 80, Zhang teaches that the CD16 coding sequence is under control of a heterologous promoter. See, e.g., paragraphs 2, 11, 96.
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.
Claims 1-2, 11-12, 15-16, 22-23, 25-26, 43-46, 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0031749 A1 to Basar et al.; in view of Baek et al. (2013) “Ex vivo expansion of natural killer cells using cryopreserved irradiated feeder cells” Anticancer Research, 33(5), 2011-2019.
US 2022/0031749 A1 to Basar et al. claims priority to 11/28/2018 based on U.S. Provisional Application No. 62/772,406. The teachings relied upon in this rejection find written support in the priority document.
Regarding claim 1, Basar teaches natural killer (NK) cells possessing loss-of-function of CISH and TGFβRII, thereby increasing their functionality and enhancing their antitumor cytotoxicity. The NK cells do not express T-cell marker CD3. See paragraphs 6, 10, 15, 32, 35, 119, 279-284; see also paragraphs 4, 8, 13, 113, 235-240 of the priority document for written support.
Basar does not teach that the NK cells express endogenous genes encoding NKp30, NKp44, NKp46 and CD158b, as instantly claimed.
Prior to the effective filing date of the instantly claimed invention, Baek teaches that NKp30, NKp44, NKp46 and CD158b are surface markers of NK cells. See Abstract; pg. 2013-2014, bridging paragraph; Figure 4.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Basar by selecting cells endogenously expressing NKp30, NKp44, NKp46 and CD158b, as taught by Baek, with a reasonable expectation of success because Basar teaches the modification of NK cells, and NKp30, NKp44, NKp46 and CD158b are surface markers endogenously expressed by NK cells.
For these reasons, claim 1 would have been prima facie obvious over the cited references.
Regarding claim 2, Basar teaches the NK cell comprises an insertion of an exogenous nucleic acid construct into a genomic locus harboring a CISH or TGFβRII gene. See, e.g., paragraphs 12, 54; see also paragraphs 10, 52 of the priority document for written support.
Regarding claim 11, Basar teaches the NK cells are derived from pluripotent stem cells. See, e.g., paragraph 120; see also paragraph 114 of the priority document for written support.
Regarding claim 12, Basar teaches the NK cells are derived from induced pluripotent stem cells or embryonic stem cells. See, e.g., paragraph 120; see also paragraph 114 of the priority document for written support.
Regarding claim 15, Basar teaches genetically modifying the pluripotent stem cells. See, e.g., paragraph 102; see also paragraph 98 of the priority document for written support.
Regarding claim 16, Basar teaches the NK cell comprises an insertion of an exogenous nucleic acid construct into a genomic locus harboring a CISH or TGFβRII gene. See, e.g., paragraphs 12, 54; see also paragraphs 10, 52 of the priority document for written support.
Regarding claim 22, Basar teaches the NK cells are obtained by editing a genomic locus with an RNA-guide endonuclease or a Cas9 nuclease. See, e.g., paragraphs 7, 32, 51; see also paragraphs 5, 30, 49 of the priority document for written support.
Regarding claim 23, Basar teaches the NK cells are obtained by editing a genomic locus with an RNA-guide endonuclease or a Cas9 nuclease. See, e.g., paragraphs 7, 32, 51; see also paragraphs 5, 30, 49 of the priority document for written support.
Regarding claim 25, since the RNA-guided endonuclease would target the gene copies on both alleles, Basar is found to teach or fairly suggest editing both genomic loci encoding CISH and TGFβRII. In addition, Basar describes “biallelic” genomic modification of the cells. See, e.g., paragraph 72; see also paragraph 66 of the priority document for written support. For these reasons, the limitations of the claim would have been prima facie obvious over the cited references.
Regarding claim 26, Basar does not teach that the different genomic modifications have been edited by a different RNA-guided nuclease, as instantly claimed. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, both the claims and the prior art provide NK cells modified with an RNA-guided nuclease. Therefore, the process of making the claimed NK cell in claim 26 is substantially similar to the product-by-process limitations taught by the prior art. The product-by-process limitations recited by claim 26 are not found to necessarily imply a structure that patentably distinguishes the instantly claimed NK cell from that found in the prior art. For these reasons, the product of claim 26 would have been prima facie obvious over the prior art. The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing a nonobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 799, 803, 218 USPQ 289, 292-33 (Fed. Cir. 1983). See MPEP 2113.
Regarding claim 43, Basar teaches a population of cells comprising the modified NK cell. See, e.g., paragraph 20; see also paragraph 18 of the priority document for written support.
Regarding claim 44, Basar teaches a pharmaceutical composition comprising a population of cells comprising the modified NK cell. See, e.g., paragraph 20; see also paragraph 18 of the priority document for written support.
Regarding claim 45, Basar does not teach the ranges for the cell numbers and purity as claimed in claim 45 "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In this case, differences in cell number and purity will not support the patentability of subject matter taught or fairly suggested by the prior art unless there is evidence indicating such parameters are critical. As set forth above, a composition of modifieds NK cells, as claimed, would have been prima facie obvious over the cited references, and there is no evidence of record that the broadly-recited ranges for the cell numbers and purity, as claimed in claim 45, are critical. Accordingly, the claimed ranges recited in claim 45 would have been prima facie obvious over the prior art, absent a secondary consideration. See MPEP 2144.05.
Regarding claim 46, Basar teaches that the NK cells are reprogrammed to express a CAR or TCR by insertion of a coding vector into the genome. See, e.g., paragraphs 12, 54; see also paragraphs 10, 52 of the priority document for written support. Since the reprogramming factor is integrated into the genome, the vector is not an episomal expression construct. For these reasons, the limitations of the claim are taught or fairly suggested by the cited references.
Regarding claim 50, Basar teaches genetically modifying the CISH and TGFβRII genomic loci of NK cells without introducing a reprogramming factor from an exogenous nucleic acid
construct. See, e.g., paragraphs 279-284; see also, e.g., paragraphs 235-240 of the priority document for written support. Accordingly, the limitations of the claim are taught or fairly suggested by the cited references.
Regarding claim 51, Basar teaches genetically modifying the CISH and TGFβRII genomic loci of NK cells without introducing a reprogramming factor from an exogenous nucleic acid construct. See, e.g., paragraphs 279-284; see also, e.g., paragraphs 235-240 of the priority document for written support. Accordingly, the limitations of the claim are taught or fairly suggested by the cited references.
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.
Claim 30 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/250,422 (reference to claim listing filed on 11/28/2025). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claim. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The reference claims recite a modified NK cell exhibiting a loss-of-function of TGFβR2 and CISH. See, e.g., claim 1.
Claim 80 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/250,422 (reference to claim listing filed on 11/28/2025); in view of US 2018/0273903 A1 to Zhang et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The reference claims recite a modified NK cell exhibiting a loss-of-function of TGFβR2 and CISH. See, e.g., claim 1.
The reference claims do not recite that the NK cells comprises an exogenous nucleic acid expression construct encoding a CD16 protein.
Prior to the effective filing date of the instantly claimed invention, Zhang is relevant prior art for teaching modified NK cells comprising an exogenous nucleic acid expression construct encoding a CD16 protein. The CD16 protein is a modified CD16 protein resistant to ADAM17 cleavage and having higher affinity for IgG than wildtype CD16. See, e.g., paragraphs 2, 11, 96.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by introducing an exogenous nucleic acid expression construct encoding a CD16 protein as taught by Zhang, with a reasonable expectation of success because Zhang provides a modified CD16 protein that is tant to ADAM17 cleavage and has higher affinity for IgG than wildtype CD16.
Zhang further teaches that the CD16 coding sequence is under control of a heterologous promoter. See, e.g., paragraphs 2, 11, 96.
Claims 1-2, 11-12, 15-16, 22-23, 25-26, 43-46, 50-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/250,422 (reference to claim listing filed on 11/28/2025); in view of US 2022/0031749 A1 to Basar et al.; and Baek et al. (2013) “Ex vivo expansion of natural killer cells using cryopreserved irradiated feeder cells” Anticancer Research, 33(5), 2011-2019. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
US 2022/0031749 A1 to Basar et al. claims priority to 11/28/2018 based on U.S. Provisional Application No. 62/772,406. The teachings relied upon in this rejection find written support in the priority document.
Regarding claim 1, the reference claims recite a modified NK cell exhibiting a loss-of-function of TGFβR2 and CISH. See, e.g., claim 1.
The reference claims do not recite that the NK cell (a) does not express endogenous CD3 and (b) expresses endogenous genes encoding NKp30, NKp44, NKp46 and CD158b, as instantly claimed.
Prior to the effective filing date of the instantly claimed invention, Basar is relevant prior art for teaching NK cells possessing loss-of-function of CISH and TGFβRII, thereby increasing their functionality and enhancing their antitumor cytotoxicity. The NK cells do not express T-cell marker CD3. See paragraphs 6, 10, 15, 32, 35, 119, 279-284; see also paragraphs 4, 8, 13, 113, 235-240 of the priority document for written support.
In addition, Baek is relevant prior art for teaching that NKp30, NKp44, NKp46 and CD158b are surface markers of NK cells. See Abstract; pg. 2013-2014, bridging paragraph; Figure 4.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by selecting cells that (a) do not endogenously express CD3 and (b) do endogenously expressing NKp30, NKp44, NKp46 and CD158b, as taught by Basar and Baek combined, with a reasonable expectation of success because the reference claims are directed to the modification of NK cells, and CD3-NKp30+NKp44+NKp46+CD158b+ is a phenotype used to characterize and identify NK cells.
For these reasons, claim 1 would have been prima facie obvious over the cited references.
Regarding claim 2, Basar teaches the NK cell comprises an insertion of an exogenous nucleic acid construct into a genomic locus harboring a CISH or TGFβRII gene. See, e.g., paragraphs 12, 54; see also paragraphs 10, 52 of the priority document for written support.
Regarding claim 11, Basar teaches the NK cells are derived from pluripotent stem cells. See, e.g., paragraph 120; see also paragraph 114 of the priority document for written support.
Regarding claim 12, Basar teaches the NK cells are derived from induced pluripotent stem cells or embryonic stem cells. See, e.g., paragraph 120; see also paragraph 114 of the priority document for written support.
Regarding claim 15, Basar teaches genetically modifying the pluripotent stem cells. See, e.g., paragraph 102; see also paragraph 98 of the priority document for written support.
Regarding claim 16, Basar teaches the NK cell comprises an insertion of an exogenous nucleic acid construct into a genomic locus harboring a CISH or TGFβRII gene. See, e.g., paragraphs 12, 54; see also paragraphs 10, 52 of the priority document for written support.
Regarding claim 22, Basar teaches the NK cells are obtained by editing a genomic locus with an RNA-guide endonuclease or a Cas9 nuclease. See, e.g., paragraphs 7, 32, 51; see also paragraphs 5, 30, 49 of the priority document for written support.
Regarding claim 23, Basar teaches the NK cells are obtained by editing a genomic locus with an RNA-guide endonuclease or a Cas9 nuclease. See, e.g., paragraphs 7, 32, 51; see also paragraphs 5, 30, 49 of the priority document for written support.
Regarding claim 25, since the RNA-guided endonuclease would target the gene copies on both alleles, Basar is found to teach or fairly suggest editing both genomic loci encoding CISH and TGFβRII. In addition, Basar describes “biallelic” genomic modification of the cells. See, e.g., paragraph 72; see also paragraph 66 of the priority document for written support. For these reasons, the limitations of the claim would have been prima facie obvious over the cited references.
Regarding claim 26, the reference claims and Basar do not teach that the different genomic modifications have been edited by a different RNA-guided nuclease, as instantly claimed. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, both the claims and the cited references provide NK cells modified with an RNA-guided nuclease. Therefore, the process of making the claimed NK cell in claim 26 is substantially similar to the product-by-process limitations taught by the cited references. The product-by-process limitations recited by claim 26 are not found to necessarily imply a structure that patentably distinguishes the instantly claimed NK cell from that found in the cited references. For these reasons, the product of claim 26 would have been prima facie obvious over the cited references. The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the cited references, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing a nonobvious difference between the claimed product and the cited product. In re Marosi, 710 F.2d 799, 803, 218 USPQ 289, 292-33 (Fed. Cir. 1983). See MPEP 2113.
Regarding claim 43, Basar teaches a population of cells comprising the modified NK cell. See, e.g., paragraph 20; see also paragraph 18 of the priority document for written support.
Regarding claim 44, Basar teaches a pharmaceutical composition comprising a population of cells comprising the modified NK cell. See, e.g., paragraph 20; see also paragraph 18 of the priority document for written support.
Regarding claim 45, the reference claims and Basar do not teach the ranges for the cell numbers and purity as claimed in claim 45 "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In this case, differences in cell number and purity will not support the patentability of subject matter taught or fairly suggested by the cited references unless there is evidence indicating such parameters are critical. As set forth above, a composition of modifieds NK cells, as claimed, would have been prima facie obvious over the cited references, and there is no evidence of record that the broadly-recited ranges for the cell numbers and purity, as claimed in claim 45, are critical. Accordingly, the claimed ranges recited in claim 45 would have been prima facie obvious over the prior art, absent a secondary consideration. See MPEP 2144.05.
Regarding claim 46, Basar teaches that the NK cells are reprogrammed to express a CAR or TCR by insertion of a coding vector into the genome. See, e.g., paragraphs 12, 54; see also paragraphs 10, 52 of the priority document for written support. Since the reprogramming factor is integrated into the genome, the vector is not an episomal expression construct. For these reasons, the limitations of the claim are taught or fairly suggested by the cited references.
Regarding claim 50, Basar teaches genetically modifying the CISH and TGFβRII genomic loci of NK cells without introducing a reprogramming factor from an exogenous nucleic acid
construct. See, e.g., paragraphs 279-284; see also, e.g., paragraphs 235-240 of the priority document for written support. Accordingly, the limitations of the claim are taught or fairly suggested by the cited references.
Regarding claim 51, Basar teaches genetically modifying the CISH and TGFβRII genomic loci of NK cells without introducing a reprogramming factor from an exogenous nucleic acid construct. See, e.g., paragraphs 279-284; see also, e.g., paragraphs 235-240 of the priority document for written support. Accordingly, the limitations of the claim are taught or fairly suggested by the cited references.
Claim 30 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 17/786,753 (reference to claim listing filed on 08/28/2025). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claim. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The reference claims recite a modified NK cell exhibiting a loss-of-function of TGFβR2 and CISH. See, e.g., claims 30, 92.
Claim 80 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 17/786,753 (reference to claim listing filed on 08/28/2025); in view of US 2018/0273903 A1 to Zhang et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The reference claims recite a modified NK cell exhibiting a loss-of-function of TGFβR2 and CISH. See, e.g., claims 30, 92.
The reference claims recite the NK cell expresses an exogenous nucleic acid sequence encoding a CD16 protein. See, e.g., claim 94.
The reference claims do not recite that the CD16 coding sequence is under control of a heterologous promoter.
Prior to the effective filing date of the instantly claimed invention, Zhang is relevant prior art for teaching modified NK cells comprising an exogenous nucleic acid expression construct encoding a CD16 protein. The CD16 protein is a modified CD16 protein resistant to ADAM17 cleavage and having higher affinity for IgG than wildtype CD16. Zhang further teaches that the CD16 coding sequence is under control of a heterologous promoter. See, e.g., paragraphs 2, 11, 96.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by operably linking a heterologous promoter sequence to the exogenous nucleic acid expression construct encoding a CD16 protein, as taught by Zhang, with a reasonable expectation of success because the reference claims recite that the NK cells are modified to express an exogenous nucleic acid sequence encoding a CD16 protein, and a promoter sequence allows the NK cell to express the CD16 coding sequence, as desired.
Claims 1-2, 11-12, 15-16, 22-23, 25-26, 43-46, 50-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 17/786,753 (reference to claim listing filed on 08/28/2025); in view of US 2022/0031749 A1 to Basar et al.; and Baek et al. (2013) “Ex vivo expansion of natural killer cells using cryopreserved irradiated feeder cells” Anticancer Research, 33(5), 2011-2019. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the cited references. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
US 2022/0031749 A1 to Basar et al. claims priority to 11/28/2018 based on U.S. Provisional Application No. 62/772,406. The teachings relied upon in this rejection find written support in the priority document.
Regarding claim 1, the reference claims recite a modified NK cell exhibiting a loss-of-function of TGFβR2 and CISH. See, e.g., claims 30, 92.
The reference claims further recite that the NK cell (a) does not express endogenous CD3 and (b) does express an endogenous gene encoding a natural cytotoxicity receptor. See, e.g., claim 93.
The reference claims do not recite that the NK cell both (a) does not express endogenous CD3 and (b) expresses endogenous genes encoding NKp30, NKp44, NKp46 and CD158b, as instantly claimed.
Prior to the effective filing date of the instantly claimed invention, Basar is relevant prior art for teaching NK cells possessing loss-of-function of CISH and TGFβRII, thereby increasing their functionality and enhancing their antitumor cytotoxicity. The NK cells do not express T-cell marker CD3. See paragraphs 6, 10, 15, 32, 35, 119, 279-284; see also paragraphs 4, 8, 13, 113, 235-240 of the priority document for written support.
In addition, Baek is relevant prior art for teaching that NKp30, NKp44, NKp46 and CD158b are surface markers of NK cells. See Abstract; pg. 2013-2014, bridging paragraph; Figure 4.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by selecting cells that (a) do not endogenously express CD3 and (b) do endogenously expressing NKp30, NKp44, NKp46 and CD158b, as taught by Basar and Baek combined, with a reasonable expectation of success because the reference claims are directed to the modification of NK cells, and CD3-NKp30+NKp44+NKp46+CD158b+ is a phenotype used to characterize and identify NK cells.
For these reasons, claim 1 would have been prima facie obvious over the cited references.
Regarding claim 2, Basar teaches the NK cell comprises an insertion of an exogenous nucleic acid construct into a genomic locus harboring a CISH or TGFβRII gene. See, e.g., paragraphs 12, 54; see also paragraphs 10, 52 of the priority document for written support.
Regarding claim 11, Basar teaches the NK cells are derived from pluripotent stem cells. See, e.g., paragraph 120; see also paragraph 114 of the priority document for written support.
Regarding claim 12, the reference claims recite the NK cells are derived from induced pluripotent stem cells or embryonic stem cells. See, e.g., claims 88, 90, 92. Basar teaches the NK cells are derived from induced pluripotent stem cells or embryonic stem cells. See, e.g., paragraph 120; see also paragraph 114 of the priority document for written support.
Regarding claim 15, the reference claims recite genetically modifying the pluripotent stem cells. See, e.g., claims 88, 90, 92. Basar teaches genetically modifying the pluripotent stem cells. See, e.g., paragraph 102; see also paragraph 98 of the priority document for written support.
Regarding claim 16, Basar teaches the NK cell comprises an insertion of an exogenous nucleic acid construct into a genomic locus harboring a CISH or TGFβRII gene. See, e.g., paragraphs 12, 54; see also paragraphs 10, 52 of the priority document for written support.
Regarding claim 22, the reference claims recite the NK cells are obtained by editing a genomic locus with an RNA-guide endonuclease or a Cas12a nuclease. See, e.g., claim 30, 32. Basar teaches the NK cells are obtained by editing a genomic locus with an RNA-guide endonuclease or a Cas9 nuclease. See, e.g., paragraphs 7, 32, 51; see also paragraphs 5, 30, 49 of the priority document for written support.
Regarding claim 23, the reference claims recite the NK cells are obtained by editing a genomic locus with an RNA-guide endonuclease or a Cas12a nuclease. See, e.g., claim 30, 32. Basar teaches the NK cells are obtained by editing a genomic locus with an RNA-guide endonuclease or a Cas9 nuclease. See, e.g., paragraphs 7, 32, 51; see also paragraphs 5, 30, 49 of the priority document for written support.
Regarding claim 25, since the RNA-guided endonuclease would target the gene copies on both alleles, the reference claims and Basar are found to teach or fairly suggest editing both genomic loci encoding CISH and TGFβRII. In addition, Basar describes “biallelic” genomic modification of the cells. See, e.g., paragraph 72; see also paragraph 66 of the priority document for written support. For these reasons, the limitations of the claim would have been prima facie obvious over the cited references.
Regarding claim 26, the reference claims and Basar do not teach that the different genomic modifications have been edited by a different RNA-guided nuclease, as instantly claimed. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, both the claims and the cited references provide NK cells modified with an RNA-guided nuclease. Therefore, the process of making the claimed NK cell in claim 26 is substantially similar to the product-by-process limitations taught by the cited references. The product-by-process limitations recited by claim 26 are not found to necessarily imply a structure that patentably distinguishes the instantly claimed NK cell from that found in the cited references. For these reasons, the product of claim 26 would have been prima facie obvious over the cited references. The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the cited art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing a nonobvious difference between the claimed product and the cited product. In re Marosi, 710 F.2d 799, 803, 218 USPQ 289, 292-33 (Fed. Cir. 1983). See MPEP 2113.
Regarding claim 43, Basar teaches a population of cells comprising the modified NK cell. See, e.g., paragraph 20; see also paragraph 18 of the priority document for written support.
Regarding claim 44, Basar teaches a pharmaceutical composition comprising a population of cells comprising the modified NK cell. See, e.g., paragraph 20; see also paragraph 18 of the priority document for written support.
Regarding claim 45, the reference claims and Basar do not teach the ranges for the cell numbers and purity as claimed in claim 45 "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In this case, differences in cell number and purity will not support the patentability of subject matter taught or fairly suggested by the cited references unless there is evidence indicating such parameters are critical. As set forth above, a composition of modifieds NK cells, as claimed, would have been prima facie obvious over the cited references, and there is no evidence of record that the broadly-recited ranges for the cell numbers and purity, as claimed in claim 45, are critical. Accordingly, the claimed ranges recited in claim 45 would have been prima facie obvious over the cited references, absent a secondary consideration. See MPEP 2144.05.
Regarding claim 46, Basar teaches that the NK cells are reprogrammed to express a CAR or TCR by insertion of a coding vector into the genome. See, e.g., paragraphs 12, 54; see also paragraphs 10, 52 of the priority document for written support. Since the reprogramming factor is integrated into the genome, the vector is not an episomal expression construct. For these reasons, the limitations of the claim are taught or fairly suggested by the cited references.
Regarding claim 50, Basar teaches genetically modifying the CISH and TGFβRII genomic loci of NK cells without introducing a reprogramming factor from an exogenous nucleic acid
construct. See, e.g., paragraphs 279-284; see also, e.g., paragraphs 235-240 of the priority document for written support. Accordingly, the limitations of the claim are taught or fairly suggested by the cited references.
Regarding claim 51, Basar teaches genetically modifying the CISH and TGFβRII genomic loci of NK cells without introducing a reprogramming factor from an exogenous nucleic acid construct. See, e.g., paragraphs 279-284; see also, e.g., paragraphs 235-240 of the priority document for written support. Accordingly, the limitations of the claim are taught or fairly suggested by the cited references.
Conclusion
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631