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 Claims
Applicant’s election for continued examination without traverse of Invention group I, as well as the species election of CD19 as first antigen and CD22 as second antigen, filed in the reply on 09/30/2024 is acknowledged.
Following Applicant’s amendment on 09/30/2024, claims 6 and 16 are amended. Claim 32 is withdrawn. Claims 1-31, and 33-35 are currently pending and under examination.
Priority
The application claims benefit of provisional application 62/807,181 filed 02/18/2019. Priority date of 02/18/2019 is acknowledged.
Claim Objections
Claim 28 is objected to because of the following informalities: line 9 has a box where there should be a character. 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 3-7 and 13-16 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 handful of native and specifically modified CD3ζ polypeptides and ITAM variants, does not reasonably provide enablement for the entire scope of the myriad of potential sequences introduced by the use of terms “modified” and “variant” within these claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant to this rejection are 1) the amount of direction provided by the inventor and 2) the existence of working examples. In the instant case, the amount of direction provided by the inventor and existence of working examples disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to use the claimed invention at the time the application was filed without undue experimentation.
(1) The amount of direction provided by the inventor - The amount of guidance or direction needed to enable an invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004). Due to the high level of unpredictability in the area of generating viable and effective modified CD3ζ polypeptides, the skilled artisan would need significant guidance in reproducing all possible variations encompassed by the scope of claims 3-7 and 13-16. The specification does not teach nor imply that the limited sequences provided by the Applicant can be modified in all possible ways and at any level of complexity. The scope of “modified” includes large deletions/truncations/additions, whilst the term “variant” implies a significant level of mutation. The examples provided are insufficient, and do not serve as a principle of general application, to enable the skilled artisan to make use of the entire scope of the terms modified/variant as taught within these claims.
(2) The existence of working examples - As stated above the specification provides enablement for a handful number of CARs comprising modified CD3ζ polypeptide with ITAM variants out of all possible variations encompassed by claims 3-7 and 13-16. Therefore, one skilled in the art would be subject to undue experimentation to practice the instant invention as it is currently claimed.
In conclusion upon careful consideration of the Wands factors that are used to determine whether undue experimentation is required to practice an invention, the amount of direction provided by the inventor and the working examples provided, as filed, is not deemed sufficient to enable the skilled artisan to use the invention commensurate in scope with the instant claims at the time the application was filed without undue experimentation.
2. Claims 21-25 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention.
Specifically, the mere addition of a third CAR as taught by these claims, without any specific antigen targeted is an arbitrary choice with no further guidance provided by inventor on specific use case nor existence of working examples that effectively use an immunoresponsive cell as taught by claim 1 with the third CAR as taught by claims 21-25. As discussed above in relation to the Wands factors, one skilled in the art would be subject to undue experimentation to practice the instant invention as it is currently claimed to determine which antigens, if any at all, would be viable with the addition of a third CAR. Therefore, the amount of direction provided by the inventor and the working examples provided, as filed, is not deemed sufficient to enable the skilled artisan to use the invention commensurate in scope with the instant claims at the time the application was filed without undue experimentation.
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 5-7 and 15-18 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.
Regarding claims 5 and 15, the phrase "comprises or consists essentially of or consists of" renders the claims indefinite because it is unclear which limitations following the phrase are part of the claimed invention. The metes and bounds of the claim are unclear from the claim wording, thereby rendering the scope of the claim unascertainable. See MPEP § 2173.05(d).
Furthermore, claims 6-7 and 16-18 depend from claims 5 and 15, respectively, but they do not resolve the ambiguity introduced by the language of clams 5 and 15.
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.
Claims 2, 5 12, 15, and 25 are 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.
Claims 2, 12, and 25 depend upon previous claims and add the feature of where the antigen has a density level of more than or about 10,000 molecules per cell, between about 5,000 and 10,000 molecules per cell, or less than 5,000 molecules per cell. As the antigen density level was not mentioned in previous claims to which these claims depend, it is assumed that the antigen density level in such claims can be any number of molecules per cell. The range defined for the antigen density level within claims 2, 12, and 25 is as follows: <5,000 (0-5,000), between 5,000-10,000, or >10,000 molecules per cell. These ranges clearly cover any possible density level of antigen and thus do not add a limitation to the claims from which they depend. Rather than limiting the subject matter of their parent claims, claims 2, 12, and 25 further expand the scope of their parent claims.
Claims 5 and 15 depend from 4 and 14 respectively. Both parent claims 4 and 14 require that ITAM1 be an ITAM1 variant but dependent claims 5 and 15 require native ITAM1 (non-mutated). Rather than limiting the subject matter of their parent claims, claims 5 and 15 further expand the scope of their parent claims.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Claim Rejections - 35 USC § 102
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 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.
Claims 1, 3-6, 8, 10-11, 13-19, 21-24, 26-31, and 33-35 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Orentas et al. (WO2018045325, cited on pg. 1 of IDS filed 09/12/2023).
Regarding claims 1, 3-6, 8, 10-11, 13-19, 21-24, 26-31, and 33-35, Orentas teaches an immunotherapy composition comprising one or more isolated nucleic acid molecules encoding at least two vectors for functional chimeric antigen receptors (claim 1). In particular, Orentas discloses T cells comprising a CAR with a first antigen binding domain specific to CD20/CD19, a first intracellular domain comprising CD28, a second CAR comprising a second antigen binding domain specific to CD22, and a second intracellular domain comprising 4-1BB (Example 1, pages 78-79). Furthermore, Orentas teaches that all CD3z chains used within their given examples comprise either one, two, or three mutated ITAM motifs (pg. 23). Orentas also show that such DuoCARs are effective in treating leukaemia (Example 2, pages 79-80).
Regarding claim 35 directed to a kit, where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). The compositions anticipated above, in any suitable container or vessel for administration, would constitute a “kit”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-31, and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Orentas et al. (cited above) as applied to claims 1, 3-6, 8, 10-11, 13-19, 21-24, 26-31, and 33-35 above, and further in view of Watanabe et al. (The Journal of Immunology, 2015, 194(3): 911-920).
The teachings of Orentas as applied to claims 1, 3-6, 8, 10-11, 13-19, 21-24, 26-31, and 33-35 is discussed above. However, Orentas does not specify the various molecular densities for the antigens as taught in claims 2, 7, 9, 12, 20, and 25 of the instant application. Watanabe addresses this deficiency by teaching the threshold target antigen density required to induce CAR-T cell responses in novel anti-CD20 CAR-T cells with a CD28 intracellular domain at ∼200 molecules per target cell for anti-CD20 CAR-T lytic activity and at a few thousand (≥5320 molecules) per target cell for anti-CD20 CAR-T cytokine production (Abstract, pg. 911; Discussion, pg. 918).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the CAR-T cell composition known from Orentas and combine it with the teachings of Watanabe of effective antigen density per molecule at a value below and above 5000 molecules per cell to achieve optimal CAR-T response to targeted antigens. One of ordinary skill in the art would have been motivated to use the effective CAR-T antigen density values for optimizing drug dosage, efficacy, side effects, and drug compliance. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
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.
1. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 13, 17, 84, and 86 of U.S. Patent No. 11267901 (‘901) in view of Orentas et al. (cited above) and Watanabe et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant application and patent ‘901 teach a T-cell comprising multiple chimeric antigen receptors, with an intracellular signaling domain including CD28 as co-stimulatory molecule, means of recombinant expression and a pharmaceutical composition comprising these CAR-T cells against antigens CD19 and CD22. However, patent ‘901 does not specifically teach the use of ITAM variants within the CD3ζ polypeptide portion of the intracellular signaling domain nor the values for antigen density. The teachings of Orentas and Watanabe as discussed above address these deficiencies.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the CAR-T cell composition known from patent ‘901 and combine it with the teachings of Orentas and Watanabe that show the use of ITAM variants within the CD3ζ polypeptide portion of the intracellular signaling domain and effective antigen density per molecule at values below and above 5000 molecules per cell. One of ordinary skill in the art would have been motivated to do so to achieve optimal CAR-T response to targeted antigens as well as optimizing the pharmaceutical CAR-T composition for drug dosage, efficacy, side effects, and drug compliance. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made and the conflicting claims are not patentably distinct from each other.
2. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16-25, 27-28, and 31 of U.S. Patent No. 12018077 (‘077) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above.
3. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-23, 29-30, 32-34, and 38 of U.S. Patent No. 12263220 (‘220) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above.
4. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 9, and 20 of copending Application No. 17/583,117 (‘117) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above.
5. Claims 1-31, and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 11, 14-15, and 18 of copending Application No. 19/076,055 (‘055) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above.
6. Claims 1-31, and 33-35 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-20, 22-23, and 26 of copending Application No. 18/622,315 (‘315) in view of Orentas et al. (cited above) and Watanabe et al. for the same reasons discussed above. In addition, while application ‘315 targets CD56 as target antigen for the first CAR, it would have been obvious to one of ordinary skill in the art to use the teachings of Orentas et al. and Watanabe et al. to modify the first CAR target antigen from CD56 to CD19 in order to more specifically target certain tumor antigens. This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS GEORGE whose telephone number is (571)270-0340. The examiner can normally be reached M-F 8:30am - 5pm EST.
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/DENNIS GEORGE/Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644
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