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 .
Application Status
Applicant’s response filed May 27, 2026 is acknowledged. Claims 1-46, and 48-66 are pending.
Restriction/Election
Applicant’s election without traverse of Group I (claims 1-16, 28-33, and 35-46) in the response filed on May 27, 2026 is acknowledged. Claims 17-27, 34, and 48-66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Claims 1-16, 28-33, and 35-46 are under consideration hereinafter.
Priority
Applicant’s priority claims to Application Nos. 63/158,313 and PCT/US22/19333 are acknowledged. Claims 1-16, 28-33, and 35-46 find support in Application No. 63/158,313. The effective filing date of the claims under examination is March 8, 2021.
Drawings
The drawings are objected to because of the following informalities:
The view labelled “FIG. 26F” on sheet 72/73 should be amended to recite “FIG. 23F.”
Appropriate correction is required.
Specification
The specification is objected to because of the following informalities:
The disclosure is objected to because it contains embedded hyperlinks and/or other forms of browser-executable code, e.g., “www.imgt.org” (pg. 68), “www.clinicaltrial.gov” (pg. 118), “https ://www. qiagenbioinformatics.com/products/ingenuitypathway-analysis,” (pg. 127), etc. Applicant is required to delete the embedded hyperlinks and/or other forms 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 correction is required.
Claim Objections
Claims 16, and 43-44 are objected to because of the following informalities:
Claim 16 recites “the antigen on a target cell.” It is clear that this phrase refers to the previous “antigen on a target cell” of claim 2. It would be preferable to amend the claim to recite “the antigen on the target cell,” accordingly.
Claims 43-44 recite “the nucleic acid encoding an exogenous TCR and/or CAR.” It is clear that this phrase refers to the previous “nucleic acid encoding an exogenous T cell receptor (TCR) and/or chimeric antigen receptor (CAR)” of claim 33. It would be preferable to amend the claim to recite “the nucleic acid encoding the exogenous TCR and/or CAR,” accordingly.
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.
Claims 8, 13, and 41-42 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 8 recites a “high affinity TCR.” The term “high affinity” is a relative term. Neither the claim nor specification provide a standard for ascertaining the requisite degree of “high affinity” required of the TCRs. Accordingly, one of ordinary skill in the art would not be reasonably apprised of the scope of the TCRs encompassed by the claim.
Claim 13 recites that “the exogenous CAR comprises a transmembrane domain selected from the group consisting of an artificial hydrophobic sequence and transmembrane domain of a type I transmembrane protein, an alpha, beta, or zeta chain of a T cell receptor, CD28, CD3 epsilon, CD45,CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.” The phrasing of the claim is confusing, because it is not clear how the phrase “an artificial hydrophobic sequence and transmembrane domain of a type I transmembrane protein” applies to the other listed terms in the grouping. For example, it is not clear whether “an artificial hydrophobic sequence,” and “transmembrane domain of a type I transmembrane protein,” are independent members of the grouping, such that the selected transmembrane domain may be an artificial hydrophobic sequence, or a transmembrane domain of a type I transmembrane protein, or any of the remaining listed terms (e.g., an alpha chain of a TCR), or for example, whether the selected transmembrane domain must include “an artificial hydrophobic sequence,” derived from one of the recited proteins (e.g., CD28), and a “transmembrane domain” of one of the recited proteins. The members of the grouping from which the transmembrane domain is selected are unclear, which renders the claim indefinite.
Claim 41 recites the term “sufficiently complementary.” The term “sufficiently” is a relative term. Neither the claim nor specification provide a standard for ascertaining the requisite degree of complementarity which would be “sufficient.” Accordingly, one of ordinary skill in the art would not be reasonably apprised of the scope of the guide RNAs encompassed by the claim.
Claim 42 is rejected for depending from claim 41 and failing to remedy the indefiniteness. Although the claim refers to specific sequences, the guide RNA need only comprise “a nucleic acid sequence” set forth in one of the recited SEQ ID NOs. This does not sufficiently clarify the scope of “sufficiently complementary,” or further limit the structure of the guide RNA so as to resolve the indefiniteness of claim 41 described above.
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 9 and 37 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 9 recites that “the exogenous CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular domain.” The specification states that “CARs of the present disclosure comprise an antigen binding domain, a transmembrane domain, and an intracellular domain” (pg. 45, line 10-11). Thus, the CAR of claim 2 inherently comprises the elements recited in claim 9. Claim 9 fails to further limit the subject matter of the claim upon which it depends.
Claim 37 recites that the “CRISPR system comprises a CRISPR nuclease and a guide RNA.” Claim 33 recites “a CRISPR system.” The specification teaches that “in the context of a CRISPR system, formation of a CRISPR complex (comprising a guide sequence… complexed with one or more Cas proteins) results in cleavage of one or both strands in or near… the target sequence” (pg. 35, lines 28-31). Thus, the “CRISPR system” of claim 33 inherently comprises the elements recited in instant claim 37, i.e., a CRISPR nuclease (“one or more Cas proteins”), and a guide RNA (“guide sequence… complexed with one or more Cas proteins”).
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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 1-16, 28, and 31-32 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Pg. 42
Claims 1-16, 28, and 31-32 are directed to a “modified immune cell or precursor cell thereof.” The invention encompasses immune cells or precursor cells thereof which are modified in vivo (pg. 42 line 20-27). The invention also encompasses human cells (pg. 6, line 13). Neither the specification nor claims expressly exclude cells within a human organism comprising the system elements. Thus, the term “modified immune cell or precursor cell thereof” could reasonably be interpreted as encompassing cells within a human organism, which is non-statutory subject matter.
Claims 29-30 are not included in this rejection, because the term “autologous cell” is interpreted as a cell obtained from (i.e., removed/isolated from) an individual (pg. 23, lines 1-2), which does not read on a cell within a human organism. Similarly, a “cell isolated from a human subject” does not read on a cell within a human organism.
Claim Rejections - 35 USC § 102 – Sade-Feldman
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 1-16, 28-33, 35-40, and 43-46 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Sade-Feldman (Sade-Feldman et al., WO 2018/209324 A2, published 15 November 2018).
Regarding claims 1 and 31, Sade-Feldman teaches a modified immune cell, which is a T cell, comprising a modification in an endogenous gene locus encoding SOX and/or ID3, wherein the modification downregulates the expression of endogenous SOX and/or ID3 (“31. The population of CD8+ T cells according to any of claims 23 to 30, wherein the cells are modulated to decrease activity or expression of one or more genes or polypeptides selected from… ID3,” pg. 279; “the population of CD8+ T cells are modulated to decrease activity or expression of… ID3,” [0023]).
Regarding claim 2, Sade-Feldman teaches the modified immune cell further comprises an exogenous T cell receptor (TCR) and/or chimeric antigen receptor (CAR) comprising affinity for an antigen on a target cell (“the immune cells or immune cell populations as taught herein may be used for adoptive cell transfer (ACT)… The cells may be further modified as discussed herein. The cells may express… a chimeric antigen receptor (CAR),” [0304]; [0305]-[0322]; “the immune cell may, in addition to a CAR or exogenous TCR as described herein…,” [0323]; “CRISPR systems may be delivered to an immune cell… cells are editing ex vivo… Editing may be performed for example to insert or knock-in an exogenous gene, such as an exogenous gene encoding a CAR or a TCR,” [0343]).
Regarding claim 3, the claim is interpreted as requiring a modified immune cell or precursor thereof comprising a substitution, an insertion, a deletion, or an insertion/deletion in an endogenous gene locus encoding SOX and/or ID3. Sade-Feldman teaches that the modification is made with “a genetic modifying agent” (“the one or more genes are modulated with a genetic modifying agent,” [0025]). Sade-Feldman teaches that genetic modifying agents may comprise a CRISPR system ([0411]). Sade-Feldman teaches that modification with a CRISPR system results in insertions or deletions which inactivate the targeted gene ([0344]). Thus, Sade-Feldman teaches a modified immune cell or precursor thereof comprising an insertion or deletion, or an insertion/deletion in an endogenous gene locus encoding SOX and/or ID3.
Regarding claims 4-7, the claims are product-by-process claims and therefore read on a cell produced by any means that would provide a modified immune cell or precursor thereof having the same structural characteristics of a cell produced by the process recited in the claims (see MPEP § 2113). With regard to the structure implied by the process steps recited in the claims, the originally filed specification states that CRISPR systems may generate cells comprising substitutions, insertions, deletions, or insertion/deletions (pg. 39, lines 12-15). With respect to the instantly claimed guide RNA sequences set forth in SEQ ID NOs: 1-10, the specification does not appear to provide any specific structure conferred to cells by use of the guide RNA sequences, e.g., by providing genomic sequencing data, or the like. In view of this, the skilled artisan would conclude, absent any evidence to the contrary, that the cells of instant claims 4-7 are modified immune cells or precursors thereof comprising a substitution, an insertion, a deletion, or an insertion/deletion in an endogenous gene locus encoding SOX and/or ID3. As stated above with respect to claim 3, Sade-Feldman teaches a modified immune cell or precursor thereof comprising an insertion, a deletion, or an insertion/deletion in an endogenous gene locus encoding SOX and/or ID3 ([0023]-[0025]; [0344]; [0411]).
Regarding claim 8, in view of the indefiniteness describe above, the term “high affinity” will be interpreted as a level of affinity which allows for recognition of a particular antigen. Sade-Feldman teaches an exogenous TCR which has affinity for a particular antigen (“a TCR recognizing tyrosinase tumor antigen,” [0331]).
Regarding claims 9-10, Sade-Feldman teaches the exogenous CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the antigen binding domain is an antibody, antibody fragment, or scFv ([0314]).
Regarding claims 11-12, Sade-Feldman teaches the exogenous CAR further comprises a hinge domain, wherein the hinge domain is an Fc fragment of an antibody, or a hinge region or CH3 region of an antibody ([0315]).
Regarding claim 13, in view of the indefiniteness described above, the group members are interpreted as an artificial hydrophobic sequence, and transmembrane domains from any of the listed species. Sade-Feldman teaches the exogenous CAR comprises a transmembrane domain which is an artificial hydrophobic sequence, or a transmembrane domain from CD28, CD45, or CD134 ([0316]).
Regarding claim 14, Sade-Feldman teaches the exogenous CAR comprises an intracellular domain comprising a co-stimulatory domain of CD28 or OX40 ([0317]).
Regarding claim 15, Sade-Feldman teaches the exogenous CAR comprises an intracellular domain comprising an intracellular signaling domain which is a cytoplasmic signaling domain of CD3 zeta chain, or TCR zeta ([0317]-[0319]).
Regarding claim 16, Sade-Feldman teaches the antigen may be a tumor-associated antigen (TAA) ([0305]; [0309]).
Regarding claims 28 and 32, with respect to the function of “resistance to T cell exhaustion and/or T cell dysfunction,” the structure of the modified immune cell taught by Sade-Feldman is substantially identical to that of the claims, and therefore, the claimed properties or functions are presumed to be inherent to Sade-Feldman’s modified immune cell. See MPEP 2112.01(I).
Regarding claim 29, Sade-Feldman teaches the modified immune cell is an autologous cell ([0029]; [0304]; [0332]).
Regarding claim 30, Sade-Feldman teaches modified immune cell is isolated from a human subject (“patient.. typically and preferably denote humans,” [0097]; [0304]; [0361]-[0372]).
0036
Regarding claim 33, Sade-Feldman teaches a method for generating a modified immune cell comprising introducing into an immune cell a CRISPR system comprising one or more polypeptides and/or nucleic acids capable of downregulating gene expression of endogenous SOX and/or ID3; and introducing into the immune cell a nucleic acid encoding an exogenous TCR and/or CAR, wherein the exogenous TCR and/or CAR comprise affinity for an antigen on a target cell (“a method of manufacturing cells for use in adoptive cell transfer comprising: obtaining CD8+ T cells… may further comprise expressing a chimeric antigen receptor (CAR),” [0036]; “31. The population of CD8+ T cells according to any of claims 23 to 30, wherein the cells are modulated to decrease activity or expression of one or more genes or polypeptides selected from… ID3,” pg. 279; “the population of CD8+ T cells are modulated to decrease activity or expression of… ID3,” [0023]; “the one or more genes are modulated with a genetic modifying agent,” [0025]; “the genetic modifying agent may comprise a CRISPR system,” [0411]; “the CRISPR effector protein may be delivered using a nucleic acid molecule,” [0416]; “the invention involves vectors, e.g., for delivering or introducing in a cell Cas and/or RNA,” [0419]; “the immune cells or immune cell populations as taught herein may be used for adoptive cell transfer (ACT)… The cells may be further modified as discussed herein. The cells may express… a chimeric antigen receptor (CAR),” [0304]; [0305]-[0322]; “the immune cell may, in addition to a CAR or exogenous TCR as described herein…,” [0323]; [0328]; [0345]; [0354]; [0357]; [0378]; [0411]-[0481]).
Regarding claim 35, Sade-Feldman teaches the CRISPR system introduces a CRISPR-mediated modification in an endogenous gene locus for the target gene ([0344]).
Regarding claim 36, Sade-Feldman teaches the modification consists of a substitution, an insertion, a deletion, or an insertion/deletion ([0344]).
Regarding claims 37-38, Sade-Feldman teaches the CRISPR system comprises a Cas9 and a guide RNA ([0412]).
Regarding claim 39, Sade-Feldman teaches introducing a RNP complex comprising the CRISPR nuclease and guide RNA ([0508]).
Regarding claim 40, Sade-Feldman teaches introducing CRISPR systems through electroporation ([0328]; [0357]; [0461]-[0462]).
Regarding claims 43-46, Sade-Feldman teaches introducing a lentiviral vector comprising the nucleic acid encoding the exogenous TCR and/or CAR via viral transduction ([0328]; [0354]; [0357]; [0378]).
Notice to Joint Inventors
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.
Claim Rejections - 35 USC § 103 – Sade-Feldman in view of Schumann
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 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Sade-Feldman (Sade-Feldman et al., WO 2018/209324 A2, published 15 November 2018) as applied to claims 1-16, 28-33, 35-40, and 43-46 in view of Schumann (Schumann et al., November 2020, Nature Immunology, Vol. 21, pg. 1456-1466 and Supplementary Table).
In view of the indefiniteness described above, and in the interest of compact prosecution, claim 41 is interpreted hereinafter as having the same scope as claim 42. The phrase “a nucleic acid sequence set forth in any one of SEQ ID NO: 1-10” in claim 42 is interpreted as any two or more consecutive nucleotides (“a nucleic acid sequence”) set forth in one of the recited SEQ ID NOs.
The teachings of Sade-Feldman are described above and applied as to claims 1-16, 28-33, 35-40, and 43-46 therein.
Sade-Feldman does not teach any guide RNA sequences, and therefore, does not teach a guide RNA targeting ID3 which comprises a nucleic acid sequence of SEQ ID NO: 9.
However, Schumann teaches a guide RNA targeting ID3, which was used to decrease ID3 expression in T cells (pg. 1457, right col.). As shown in the attached alignment in Appendix I, Schumann’s guide RNA comprises at least two consecutive nucleotides of instant SEQ ID NO: 9 (“ID3_2,” see attached Supplementary Table).
Regarding claims 41-42, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the CRISPR-based method of modifying immune cells of Sade-Feldman with the guide RNA sequence targeting ID3 described by Schumann. It would have amounted to using a known guide RNA sequence targeting a gene in a known method (i.e., ID3), by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success that the guide RNA sequence of Schumann would be functional in the method of Sade-Feldman, and would have been motivated to use the known guide RNA sequence, because Sade-Feldman is silent as to guide RNA sequences which may be used in the method, and Schumann teaches a CRISPR-based method of modifying T cells to reduce ID3 expression, and the sequence of a functional guide RNA.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNA L PERSONS whose telephone number is (703)756-1334. The examiner can normally be reached M-F: 9-5pm.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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