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 .
Status of Application, Amendments and/or Claims
Claims 1-20 are pending and under consideration in the instant application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12 December 2024 and 09 January 2024 (2) are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
1. The disclosure is objected to because of the following informalities:
1a. The instant specification refers to SEQ ID NOs: 2 and 8, which are “skipped” (blank) sequences under ST.26 Sequence Requirements. These sequences have fewer than four specifically defined amino acids. While it is acceptable for a sequence listing to contain skipped sequences, the instant specification still recites these SEQ ID NOs with no reference to the actual amino acid sequences themselves.
This issue can be overcome by filing: (i) an amendment to the specification to replace SEQ ID NOs: 2 and 8 with the actual respective amino acid sequences; (ii) a statement that no new matter is added; and (iii) reference to a priority document with a disclosure of the sequences that correspond to the SEQ ID NO with a skipped sequence.
Appropriate correction is required.
Claim Objections
2. Claims 1, 6, 9, 10, 13, and 20 are objected to because of the following informalities:
2a. In claim 1, lines 11 and 12, after each recitation of the phrase “the amino acid sequences”, the word “of” is missing and should be inserted.
2b. In claim 6, line 5, the word “an” is missing and should be inserted before “FcRγ”.
2c. In claim 9, lines 3, 5, 8, 10, 12, 14, 17, and 20, the word “an” is missing before each recitation of “anti-CD138” or “anti-CD38” and should be inserted.
2d. In claim 9, lines 16 and 19, the word “a” is missing before each recitation of “DNA” and should be inserted.
2e. In claim 10, line 9, there is a word or phrase missing after “SEQ ID NO: 26”. It is noted that this issue could be overcome by amending line 9 to recite, for example, “the amino acid sequence of SEQ ID NO: 26[,] or an IRES peptide”.
2f. In claim 13, lines 3, 5, 7, 9, 11, 13, 14, and 16, the word “an” is missing before each recitation of “anti-CD138” or “anti-CD38” and should be inserted.
2g. In claim 20, line 1, after the word “cancer”, the term “is” is missing and should be inserted.
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.
3. Claims 1-20 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.
3a. Claims 1-20 are rejected as being indefinite because claims 1, 2, 8, and 13 refer to SEQ ID NOs: 2 and 8. The sequence listings for SEQ ID NOs: 2 and 8 do not contain any sequence data because these sequences are less than 4 specifically defined amino acids. Therefore, it is not clear what sequences are encompassed by SEQ ID NOs: 2 and 8 as claimed and one skilled in the art would not be reasonably apprised of the scope of the invention. Please note that this issue could be overcome by amending the claims to replace SEQ ID NOs: 2 and 8 with the actual amino acid sequences.
3b. Claim 6 recites the limitation "the peptide linker" in line 8. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 6 depends, does not recite a “peptide linker”.
Claim Rejections - 35 USC § 112(a)
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.
4. Claim 19 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating multiple myeloma in a subject in need thereof comprising administering an effective amount of T-cells according to claim 1, does not reasonably provide enablement for a method of treating cancer in a subject in need thereof comprising administering an effective amount of T-cells according to claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 19 of the instant application is directed to a method of treating multiple myeloma in a subject in need thereof comprising administering an effective amount of T-cells according to claim 1.
The specification of the instant application teaches generating human T cells comprising two different chimeric antigen receptors (CARs), one directed against CD138 and the other directed against CD38 (page 35, [158] through page 38, [169]). Example 3 discloses an in vivo human multiple myeloma (MM) model wherein modified T cells transduced with the two different CARs are injected into the mouse model (page 39, [176-180]). The specification indicates that MM mice treated with Dual-CAR T cells show significantly better survival rates in comparison to those treated with CD38 CAR T cells and untreated groups (page 40, [183], [187]; Figures 6, 8).
Regarding the breadth of the term “cancer” in claim 19, the specification of the instant application only teaches administration of the T cells of the invention treats cancer, such as multiple myeloma (page 7, 28-29]; page 31, [135]). The specification does not provide a definition or any other types of cancer that are encompassed by the invention.
The specification and prior art do not teach any methods or working examples that indicate treatment of all possible cancers by administration of T cells modified to express an anti-CD138 CAR and an anti-CD38 CAR. A large quantity of experimentation would be required to determine what other cancers, besides multiple myeloma, would be responsive/amenable to treatment with T cells modified to express an anti-CD138 CAR and an anti-CD38 CAR because cancers are diverse and all may not involve CD138 and CD38. Such experimentation is undue. For example, undue experimentation would be required of the skilled artisan to determine the optimal quantity, duration, and route of administration of the T cells modified to express an anti-CD138 CAR and an anti-CD38 CAR for treatment all possible cancers. The limited guidance in the specification is not adequate and is merely an invitation to the artisan to use the current invention as a starting point for further experimentation. Such trial and error experimentation is considered undue. The courts have stated that patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be patentable. Tossing out the mere germ of an idea does not constitute an enabling disclosure. Reasonable detail must be provided in order to enable members of the public to understand and carry out the invention. See Genentech v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 (1997).
Furthermore, Applicant is reminded that a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. See In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971); In re Soll, 97 F.2d 623, 634, 38 USPQ 189, 191 (CCPA 1938; In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). At the time of filing the instant application, one skilled in the art would not be able to predict that administration of T cells modified to express an anti-CD138 CAR and an anti-CD38 CAR would treat all possible cancers (other than multiple myeloma). The limited teachings of the specification are not adequate guidance, but are merely an invitation for the artisan to use the current invention as a starting point for further experimentation. For instance, White et al. (J Adolescent Health 52: S1-S7, 2013) teach that cancer is the result of multiple alterations in processes that control cell proliferation, invasion, and spread (page S2, column 1, 1st full paragraph). White et al. continue to disclose that nearly all cancers result from multiple factors that influence these processes over an extended time, such factors including genetic mutations, environmental interactions, and lifestyle (page S2, column 1, 1st and 2nd full paragraphs; page S5, column 1, last paragraph).
Regarding CD38 and solid tumors, the post-filing reference of Konen et al. (Cells 9(52): 2020, doi:10.3390/cells9010052) states:
“The understanding of how this immune cell marker [CD38] may influence the progression and immune evasion within solid tumors is a relatively new field. In solid tumors, the data largely indicate an immunosuppressive role for CD38, indicating the potential to utilize CD38 inhibitors in these tumors. However, the implementation of a CD38-targeting strategy in solid tumors would likely be more complicated than it may first appear. Far from inhibiting a simple enzymatic reaction, CD38 inhibition would likely have unforeseen effects, as it is a highly complex molecule capable of numerous functions. Additional research is required in order for the rational and efficacious delivery of these inhibitors, either alone or in combination with other immunotherapeutic agents, to fully realize their potential.” (page 2, 1st full paragraph)
The instant specification also teaches that despite the fact that CD138 is considered as one of the most promising markers, in a phase I/II study with immunoconjugate BT062 used as a single agent, only 1 out of 23 patients showed an objective clinical response (see page 3, [9]). The specification continues to indicate that CD138 is expressed on many mature epithelial cells and liver and skin toxicity was observed in those clinical trials (indicating that significant side effects of CAR-T treatment directing CD138 may be expected) (page 3, [9]). The state of the art at the time of filing the instant application also teaches that CD138 is dysregulated in many cancers. Some cancers have low expression of CD138 and are associated with a worse prognosis while conversely, other cancers have high expression and are also correlated with a poor prognosis (Teng et al., Matrix Biol 31: 3-16, 2012). Therefore, CD138 expression may have differing functions, depending upon the type of cancer and one skilled in the art would not want to inhibit CD138 in cancers that already have a reduction in CD138. In view of the teachings of the instant specification and the state of the art, one skilled in the art would not be able to predict which cancers would be amenable to treatment with T cells modified to express an anti-CD138 CAR and an anti-CD38 CAR, other than multiple myeloma.
Due to the large quantity of experimentation necessary to treat all cancers; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; the unpredictability of treating all cancers; and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
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.
5. Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,944,644. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of the claims are directed to a T-cell genetically modified to express at least two distinct chimeric antigen receptors (CARs), wherein the first CAR comprises an antigen binding domain that specifically binds to CD138 and the second CAR comprises an antigen binding domain that specifically binds to CD38.
Claim 1 of the instant application recites a T-cell genetically modified to express at least two distinct separate chimeric antigen receptors (CARs), wherein the first CAR comprises an antigen binding domain that binds specifically to CD138 (anti-CD138 CAR) and the second CAR comprises an antigen binding domain that binds specifically to CD38 (anti-CD38 CAR), wherein one of the CARs comprises an activation domain and is devoid of a costimulatory domain and the other CAR comprises a costimulatory domain and is devoid of an activation domain, wherein the anti-CD138 CAR comprises a VL domain comprising three complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NO: 1, 2 and 3 and a VH domain comprising three CDRs comprising the amino sequences of SEQ ID NO: 4, 5 and 6 and wherein the anti-CD38 CAR comprises a VL domain comprising three CDRs comprising the amino acid sequences SEQ ID NO: 7, 8 and 9 and a VH domain comprising three CDRs comprising the amino sequences SEQ ID NO: 10, 11 and 12.
Meanwhile, claim 1 of the ‘644 patent recites a T-cell genetically modified to express at least two distinct separate chimeric antigen receptors (CARs), wherein the first CAR comprises an antigen binding domain that binds specifically to CD138 and the second CAR comprises an antigen binding domain that binds specifically to CD38, wherein one of the CARs comprises an activation domain and is devoid of a costimulatory domain and the other CAR comprises a costimulatory domain and is devoid of an activation domain.
Claim 3 of the instant application and claim 2 of the ‘644 patent recite that the antigen binding domain that binds specifically to CD138 is a single chain variable fragment (anti-CD138 scFv) and the antigen binding domain that binds specifically to CD38 is a single chain variable fragment (anti-CD38 scFv).
Claim 4 of the instant application and claim 3 of the ‘644 patent recite that the anti-CD138 scFv comprises a VL domain having the amino acid sequence of SEQ ID NO: 13 and a VH domain having the amino acid sequence of SEQ ID NO: 14; and/or wherein the anti-CD38 scFv domain comprises a VL domain having the amino acid sequence of SEQ ID NO: 15 and a VH domain having the amino acid sequence of SEQ ID NO: 16, wherein the VL and VH domains are bound by a peptide linker.
Claims 9-11 of the instant application and claims 8-10 of the ‘644 patent recite the same limitations regarding the DNA construct comprised in the claimed T-cell.
Instant claim 12 and claim 11 of the ‘644 patent recite that the T cell is selected from a CD4+ T cell and a CD8+ T cell.
Claims 13-17 of the instant application and claims 14-19 of the ‘644 patent recite the same DNA constructs and cells comprising the DNA constructs.
Instant claim 18 and claim 12 of the ‘644 patent recite a pharmaceutical composition comprising a plurality of the T cells according to claim 1.
Claims 19-20 and claim 13 of the ‘644 patent recite a method of treating multiple myeloma in a subject in need thereof comprising administering to the subject an effective amount of a plurality of the T cells according to claim 1.
It is noted that the amino acid sequences recited in the claims of the ‘644 patent are 100% identical to the same sequences recited in the instant claims.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIDGET E BUNNER whose telephone number is (571)272-0881. The examiner can normally be reached Monday-Friday 9:00 am-6:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
BEB
Art Unit 1647
20 July 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
Prosecution Insights