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 .
Claim Objections
(A)Claims 10-63, and 65-87 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot serve as the basis for another multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims 10-63, 65-87 have not been further treated on the merits.
(B)Claim 7 is objected to for the typographical error of “SEQ ID NO: 106-112” rather than ---SEQ ID NO: 107-112---.
Claims 1-87 are pending. Claims 10-63 and 65-87 have been withdrawn from consideration due to improper format. Claims 1-9 and 64 are examined on the merits.
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.
Claims 6-8 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 6 and 7 are vague and indefinite in the recitation of “Table 5” as a means for identifying the CDR sequences of the second receptor. Claim 8 is vague and indefinite in the recitation of “Table 4” as a means for identifying the extracellular binding domains of the second receptor.
Section 2173.05(s) of the M.P.E.P. states:
Reference to Figures or Tables
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parteFressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).
Thus, claims 6-8 are vague and indefinite because they are not complete in themselves.
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 6-9 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.
Section 2163 of the M.P.E.P. states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., 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. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
Claims 6 and 7 are reliant on a genus of extracellular ligand binding domain of the second receptor comprising, in part, CDRs of Table 5 having 1, 2, or 3 substitutions, deletions or insertions relative to the CDRs of Table 5.
Claims 8 and 9 are reliant on a genus of extracellular ligand binding domains of the second receptor comprising, in part, a sequence having at least 85%, at least 90%, at least 95%, at least 97% or at least 99% identity to the sequences of Table 4, or at least 85%, at least 90%, at least 95%, at least 97% or at least 99% identity to SEQ ID NO: 89-100.
It is well-known in the art that the CDR regions arranged in appropriate special orientation provide the antibody paratope which determines antigen recognition. In claims 6, and 7, variants comprising up to 3 substitutions, deletions and insertions into the CDR regions are claimed. Beyond the presence of the CDR regions in Table 5, the specification fails to provide any written description of alterations within these regions that would preserve the binding to the parent antigen, or would provide binding to another antigen having expression that was lost due to LOH in tumor cells. Claims 8 and 9 encompass variants having 85%, 90%, 95%, 97% or 99% identity to the sequences in Table 4 representing extracellular ligand binding domains. When given the broadest reasonable interpretation, the variations in sequence are permitted in any location of the amino acid sequences in Table 4, or in SEQ ID NO: 89-110, thus encompassing alterations in the CDR regions. The specification has not described a representative number of variants for each of the sequences in Table 5 or Table 4 that would serve to characterized the claimed genus. Neither has the specification correlated any minimum structure smaller than the CDRs with the required binding to all of the targeted antigens encompassed in the ligand binding domains of Tables 4 or 5. One of skill in the art would not be able to envisage an extracellular ligand binding domain of claims 6 and 7 outside of those binding domains comprising the CDRs of the heavy and light chains in Table 5, SEQ ID NO:101-106, or SEQ ID NO: 107-112, the polypeptide sequences of Table 4 or the polypeptide sequence of SEQ ID NO:89-100 as one could do with a well-described genus. One of skill in the art world reasonably conclude that applicant was not in possession of the invention at the time of filing.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Gross et al (WO2019/068007) in view of Caruso et al (Cancer Research, 2015, Vol. 75, pp. 3505-3518).
Gross et al teach a method of cancer immunotherapy by adoptive cell transfer of cells expressing chimeric antigen receptors on the surface of tumor cells and inhibitory CARs directed at allelic variants of the same or other cell surface antigens expressed by normal cells but not by the tumor due to loss of heterozygosity (page 1, paragraph [0004]). Gross et al teach that the safety of CAR-T cell therapy is determined in large part by the ability to discriminate between the tumor and healthy tissue and that a major risk is that of “off-tumor, on target toxicity resulting from extra tumoral expression of the targeted antigen *page 2, paragraph [0006]). Gross et al teach that off tumor reactivity occurs when the target antigen of the CAR-killer cells is shared with normal tissue, but if this tissue expresses another surface antigen nor present on the tumor, then the co-expression in the gene-modified cells of an inhibitory CAR targeting the non-shared normal antigen in combination with the activating CAR can prevent T cell activation against the normal cells (paragraph [0011]). Gross et al teach that the inhibitory CAR expressed on the cell surface is directed against or specifically binds to a single allelic variant of a gene selected from the group including APCDDl, or COLEC12(paragraph [0322]), which are the same non-target antigens lost in the tumor due to LOH as taught by the instant specification. Gross et al teach that HLA can be used as iCAR target (paragraph [00502]) after establishing that the tumor has lost expression of the HLA as a result of heterozygosity (paragraphs [00494]-[00498]. Gross et al teach that identified lost allele will determine the relevant iCAR for each patient and that one patient exhibited loss of HLA- A30 allele in the tumor samples and becomes hemizygous to HLA-32; patient #RC003 lost HLA-1 in the tumor sample and became hemizygous to HLA-30 which meets the limitations of claims 3 and 5, directed to HLA-A*01 and HLA-A*03.
Gross et al do not specifically teach the polynucleotide or polynucleotide system of claim 64, however this would be obvious because the T cells comprising the chimeric antigen receptors, both activating n inhibitory are engineered recombinant cells by co-expression of the activating CAR and the inhibiting CAR.
Gross et al do not specifically teach the combination of the activating CAR-T direct toward EGFR with the inhibitor CAR-T directed toward antigens on normal cells which are not expressed on tumor cells due to LOH.
Caruso et al teach that many tumors overexpress tumor-associated antigen, EGFR, relative to normal tissue and this limits the targeting of EGFR by T cells expressing chimeric antigen receptor due to the potential of for deleterious recognition of normal cells (abstract, lines 1-4).
It would have been prima facie obvious at the time prior to the effective filing date to co-express the stimulatory anti EGFR chimeric antigen with an inhibitory chimeric antigen which recognized an antigen on normal cells, wherein the antigen was not expressed on the tumor cell expressing EGFR due to LOH. One of skill in the art would have been motivated to do so because Gross et al teach that a CAR-T cell expressing a stimulatory CAR against an antigen expressed on the tumor can be engineered to express an inhibitory CAR against an antigen expressed on normal cells but not on tumor cells due to LOE; and because Caruso et al teach that the targeting of EGFR by CAR-T cells has the potential for deleterious recognition of normal cells by the EGFR CAR-T cells. One of skill in the art would be motivated to eliminate the “on target, off-tumor” effect and avoid deleterious effects therefrom in patients.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Gross et al and Caruso et al as applied to claims 1-3 and 5 above, and further in view of Niens et al (Blood, 2007, Vol. 110, pp. 3310-3315).
The combined teachings of Gross et al and Caruso et al render obvious claims 1-3 and 5 for the reasons et forth above. Gross et al teach that HLA can be used as iCAR target (paragraph [00502]) after establishing that the tumor has lost expression of the HLA as a result of heterozygosity (paragraphs [00494]-[00498]. Gross et al teach that identified lost allele will determine the relevant iCAR for each patient and that one patient exhibited loss of HLA- A30 allele in the tumor samples and becomes hemizygous to HLA-32; patient #RC003 lost HLA-1 in the tumor sample and became hemizygous to HLA-30 which meets the limitations of claims 3 and 5, directed to HLA-A*01 and HLA-A*03The combined teachings does not specifically address the second receptor comprising an extracellular ligand binding domain specific to HLA-A*02.
Niens et al teach that HLA-*01, *02 and *03 are the most common HLA-A types (page 3311, lines 3-4 under the heading “Determination of HLA-A haplotypes”).
It would have been obvious to co-express a second receptor comprising an extracellular ligand binding domain specific to HLA-A*02 in the T cell expressing an activating chimeric antigen receptor against EGFR for administration to a patient with a EGFR expressing tumor that has lost expression of HLA-A*02 due to loss of heterozygosity. One of skill in the art would have been motivated to do o by the teachings of Gross et al teach that identified lost allele will determine the relevant iCAR for each patient and the teachings of Niens et al that HLA-A*02 is one of the three most common HLA-A alleles.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 and 64 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No.11,602,544. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the patent anticipate the instant claims.
Claim 1 of ‘544 teach a T-cell comprising (a) an activating receptor comprising an extracellular ligand binding domain specific for EGFR, and (b) an inhibitory receptor specific to HLA-A*02. The claims of the patent do not teach that the HLA-A*02 expression in a EGFR positive cancer cell due LOH
Section 804 IIb of the M.P.E.P. teaches:
The specification can be used as a dictionary to learn the meaning of a term in the patent claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999)
In the instant case, the specification of the ‘544 patent teaches
In some embodiments, the EGFR+/HLA-A*02− cancer cell is derived from an EGFR+/HLA-A*02+ cell by loss of heterozygosity at HLA-A leading to loss of HLA-A*02.
Thus, instant claims 1-4 are obvious over the claims of the patent to the extent that the inhibitory receptor being specific for HLA-A*02 is specific for HLA-A*02 on the normal cell but lost on the tumor cell due to LOH.
Claims 1-9 and 64 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643