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 .
Application Status
Claims 150-177 are pending and examined on the merits herein.
Specification
The disclosure is objected to because of the following informalities:
The incorporation statement of a sequence listing references the sequence size in KB; to be compliant with ST.26 the sequence size must be disclosed in bytes.
Appropriate correction is required.
The use of the term MACSelect™ on pages 104-105, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Claim 160 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 160 depends from itself, which renders the claim indefinite as the limits of the claim are unclear.
For the purpose of compact prosecution the dependencies will be examined as follows:
Claim 160 from claim 157.
Claim Rejections - 35 USC § 112(d)
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 157-159 and 161 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.
Claim 157 recites the limitation "the vector of claim 158, wherein expression of the first shRNA is regulated by a first promoter and expression of the second shRNA is regulated by a second promoter.” This is not further limiting as claim 158 cites “the first promoter and the second promoter.”
Claim 158 recites the limitation "the vector of claim 159, wherein the first promoter and the second promoter are oriented in different directions from each other,” while claim 159 recites that the promoters are “in a head to head orientation” Therefore, claim 158 is not further limiting to claim 159 as head to head is already oriented in different directions.
Claim 159 recites the limitation "the vector of claim 160, wherein the first promoter and the second promoter are I head to head orientation,” but claim 160 cites that the promoters are in “tail to tail orientation” therefore these claims are contradictory and not further limiting.
For the purpose of compact prosecution the dependency will be examined as follows:
Claim 157 depends from claim 150,
Claim 158 from claim 157,
Claim 159 from claim 157,
Claim 161 depends from claim 159 and is therefore included in this rejection.
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.
Claims 150-151, 155-156, 162-163, 167-170, and 176-177 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Beatty (US 2016/0311917 A1; IDS entered 05/16/2023).
Regarding claims 150, 162, and 167-168, Beatty teaches an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises i) an antibody or antibody fragment comprising a human anti-mesothelin binding domain, ii) a transmembrane domain, and iii) an intracellular signaling domain comprising a stimulatory domain (claim 1). Beatty teaches a vector comprising a nucleic acid molecule encoding a CAR of any of the preceding claims (claim 76), a cell comprising the vector (claim 84), wherein the cell is a human T cell (claim 85). Beatty further teaches the CAR-expressing cell described herein can further express a molecule that modulates or regulates T cell function is an shRNA; including PD-1 and TIGIT (para 0033).
Regarding claims 151 and 163, Beatty teaches mesothelin was originally identified by Pastan and colleagues as a tumor associated antigen due to its limited expression by normal tissues and overexpression on tumors (para 0003).
Regarding claims 155 and 169, Beatty teaches wherein the encoded intracellular signaling domain comprises a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta (claim 25).
Regarding claims 156 and 170, Beatty teaches various configurations of a single vector encoding a CAR with a shRNA (Fig 47; para 0105).
Regarding claim 176, Beatty teaches the CAR-modified T cells of the present invention may be administered either alone, or as a pharmaceutical composition in combination with diluents and/or with other components such as IL-2 or other cytokines or cell populations (para 0464).
Regarding claim 177, Beatty teaches a method of treating a mammal having a disease associated with expression of mesothelin comprising administering to the mammal an effective amount of a cell comprising a CAR molecule of any of the preceding claims (claim 93).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 152-154 and 164-166 are rejected under 35 U.S.C. 103 as being unpatentable over Beatty (US 2016/0311917 A1; IDS entered 05/16/2023) as applied to claims 150-151, 155-156, 162-163, 167-170, and 176-177 above, and further in view of Loew (WO 2015/142675 A2; IDS entered 05/16/2023).
The teachings of Beatty regarding claims 150-151, 155-156, 162-163, 167-170, and 176-177 are detailed above.
Beatty does not teach wherein the cancer antigen is CD19 or CD22, associated with a B-cell blood cancer or a B-cell lymphoma.
Regarding claims 152 and 164, Loew teaches a method of treating a subject having a disease associated with expression of a tumor antigen, comprising administering to the subject an effective amount of an immune effector cell (e.g., a population of immune effector cells) comprising a chimeric antigen receptor (CAR) molecule, in combination with an agent that increases the efficacy of the immune cell, wherein: (i) the CAR molecule comprises an antigen binding domain, a transmembrane domain, and an intracellular domain comprising a costimulatory domain and/or a primary signaling domain, wherein said antigen binding domain binds to the tumor antigen associated with the disease, and said tumor antigen is CD19 or CD22 and (iv) an inhibitor of an immune inhibitory molecule (claim 2). Loew further teaches that adoptive cell transfer (ACT) therapy with autologous T-cells, especially with T- cells transduced with Chimeric Antigen Receptors (CARs), has shown promise in hematologic cancer trials (para 003). Loew further teaches that In one embodiment, the agent that inhibits the inhibitory molecule is an inhibitory nucleic acid a shRNA; wherein the inhibitory nucleic acid is linked to the nucleic acid that encodes a component of the CAR molecule (para 0087); wherein the inhibitory molecule can be PD-1 and TIGIT (para 0088).
Regarding claims 153-154 and 165-166, Loew teaches wherein the cancer is a hematologic cancer chosen from diffuse large B cell lymphoma (claims 5-6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the CAR targeting CD19 or CD22 as taught by Loew into the composition or method of treatment with immune cells expressing a vector comprising two polynucleotides encoding a mesothelin-CAR and shRNA targeting PD-1 and TIGIT as taught by Beatty. The ordinary artisan would have been motivated to do so because Loew teaches that ACT therapy with autologous T-cells, especially with T- cells transduced with CARs, has shown promise in hematologic cancer trials. Loew and Beatty are analogous arts teaching treatment of cancer with a tumor antigen targeting CAR and a shRNA to improve T cell function for adoptive cell therapy, therefore the ordinary artisan has a reasonable expectation of success to substitute the CAR targeting the CD19 and CD22 into a vector comprising two nucleotides comprising a CAR and shRNA targeting inhibitory molecules.
Claims 157-161 and 171-175 are rejected under 35 U.S.C. 103 as being unpatentable over Beatty (US 2016/0311917 A1; IDS entered 05/16/2023) as applied to claims 150-151, 155-156, 162-163, 167-170, and 176-177 above, and further in view of Liu (US 2008/0293142 A1; IDS entered 05/16/2023).
The teachings of Beatty regarding claims 150-151, 155-156, 162-163, 167-170, and 176-177 are detailed above.
Beatty does not teach wherein the first shRNA and second shRNA are regulated by separate promoters; wherein the promoters are organized in different directions; wherein the promoters are head-to-head; wherein the promoters are tail-to-tail; or wherein the promoters are RNA polymerase III promoters.
Regarding claims 157-159 and 171-173, Liu teaches an expression cassette for expressing a plurality of short hairpin (sh) RNAs, comprising a plurality of promoters, at least one of which comprises two promoters in a bidirectional promoter in a back-to-back form; and a plurality of nucleic acid sequences encoding said plurality of shRNAs, wherein each of said plurality of promoters is operationally linked to one of said plurality of nucleic acid sequences encoding said plurality of shRNAs (claim 1).
Regarding claims 160 and 174, Liu teaches promoters in tail to tail orientation in Figure 1.
Regarding claims 161 and 175, Liu teaches wherein said plurality of promoters comprises Pol III RNA promoters (claim 2).
Liu further teaches that the present invention provides shRNA expression cassettes that are straightforward and cost-effective to construct, and that are capable of stably expressing multiple shRNAs within a cell that results in silencing of mRNAs within the cell in a sequence specific manner (para 0009).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the vector construction with multiple promoters and orientation as taught by Liu into the composition or method of treatment with immune cells expressing a vector comprising two polynucleotides encoding a mesothelin-CAR and shRNA targeting PD-1 and TIGIT as taught by Beatty.
The ordinary artisan would have been motivated to do so because Liu teaches a method of construction that provides shRNA expression cassettes that are straightforward and cost-effective to construct, and that are capable of stably expressing multiple shRNAs within a cell that results in silencing of mRNAs within the cell in a sequence specific manner. The ordinary artisan has a reasonable expectation of success to construct the vector comprising multiple shRNA sequences with individual promoters in various orientations as taught by Liu to produce cost effective silencing of inhibitor shRNAs in the composition and method of treatment comprising immune cells comprising a vector comprising polynucleotides encoding a CAR and shRNAs.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of 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.
Claim 177 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11,679,129 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The patented claims teach: A method of treating cancer, comprising administering a T cell to a human subject having cancer, said T cell comprising a dual two-in-one vector that comprises (i) a first nucleotide sequence that encodes and expresses in the T cell: (a) a short hairpin RNA (shRNA) that inhibits expression of programmed cell death protein 1 (PD-1 shRNA), wherein the nucleotide sequence encoding the PD-1 shRNA consisting of SEQ ID NO:265 is regulated by a U6 Pol III promoter, and (b) an shRNA that inhibits expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT shRNA), wherein the nucleotide sequence encoding the TIGIT shRNA consisting of SEQ ID NO: 240 is regulated by a U6 Pol III promoter, wherein the two U6 Pol III promoters are oriented in different orientations from each other; and (ii) a second nucleotide sequence that encodes and expresses in the T cell a chimeric antigen receptor (CAR), wherein the CAR comprises an extracellular antigen recognition domain that binds a target antigen associated with the cancer, a transmembrane domain, and an intracellular signal transduction domain; wherein the first nucleotide sequence and the second nucleotide sequence are present on a single vector (claims 1-6).
Claim 177 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-6, 9 and 12 of U.S. Patent No. 12,285,438 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The patented claims teach: A method of treating cancer, comprising administering a human-derived T cell to a human subject having cancer, said human-derived T cell comprising (i) a first nucleotide sequence encoding a first short hairpin RNA (shRNA) that inhibits expression of Programmed Cell Death 1 (PD-1) and a second shRNA that inhibits expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT), and (ii) a second nucleotide sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an extracellular antigen recognition domain that binds a target antigen associated with the cancer, a transmembrane domain, and an intracellular signal transduction domain comprising a CD3 intracellular domain and a 4-1BB costimulatory molecule, wherein expression of the first shRNA is regulated by a first promoter and expression of the second shRNA is regulated by a second promoter, wherein the target antigen is CD19 and wherein the cancer is a CD19 positive cancer (claims 1-6, 9 and 12).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMBER K FAUST/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643