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 .
Detailed Action
This action is in response to the papers filed March 17, 2026.
Amendments
Applicant's amendments, filed March 17, 2026, is acknowledged. Applicant has cancelled Claims 1-16 and 31, amended Claims 17-18, 22-25, 28-30, and 33, and added new claims, Claims 34-38.
The amendment to the claims filed on March 17, 2026 does not comply with the requirements of 37 CFR 1.121(c). Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
The correct status of Claim 18 is (Currently amended).
Claims 17-30, and 32-38 are pending.
Election/Restrictions
Applicant has elected with traverse the invention of Group I, Claim(s) 17-28 and 32, drawn to an engineered immune cell defective for SOCS-1, and a method of using said cell in an adoptive cellular therapy for the treatment of cancer.
Within Group I, Applicant has elected without traverse the following species, wherein:
i) the alternative additional genetic modification is FAS, as recited in Claims 18 and 24; and
ii) the alternative agent to inhibit the expression and/or activity of the target molecule(s) is gene editing, as recited in Claim 31.
Response to Arguments
Applicant argues that Group II is directed to making the product of Group I, which, in light of Applicant’s species election of FAS, the Examiner finds persuasive.
Claims 17-30, and 32-38 are pending.
Claims 18-19, 25-28, and 34-38 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, e.g. Suv39h1, there being no allowable generic or linking claim.
Claims 17, 20-24, 29-30, and 32-33 are under consideration.
Priority
This application is a 371 of PCT/EP2021/71504 filed on July 30,2021.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). A certified copy of EPO 20305878.9 filed on July 30, 2020 is filed with the instant application.
Claim Objections
1. The prior objection of Claims 18, 24, and 29-30 is withdrawn in light of Applicant’s amendment to independent Claim 17 to recite SOCS1, as also recited in Claims 24 and 29-30.
Claim Rejections - 35 USC § 112
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.
2. The prior rejection of Claim(s) 18 and 29-31 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to the claims cancelling recitation of the “particularly” and “optionally” clauses.
3. The prior rejections of Claim(s) 29-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in light of Applicant’s amendment to the claims cancelling recitation of the “universal”.
4. The prior rejection of Claim 26 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to the claim to recite dependency upon Claim 19.
5. The prior rejection of Claim(s) 33 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to the claim.
6. The prior rejection of Claim 30 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to the claim.
7. The prior rejection of Claim 30 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s amendment to the claim.
8. The prior rejection of Claim 23 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s amendment cancelling “at risk of suffering from a cancer”.
9. Claims 22-23 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.
The recitation of a process limitation in Claims 22-23 is not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claims 22-23 imparts a novel or unexpected property to the claimed product, as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the engineered immune cell defective for SOCS1 were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
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.
Response to Arguments
Applicant argues that the amendments to Claims 22-23 render the rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. The recitation of a process limitation in Claims 22-23 is not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claims 22-23 imparts a novel or unexpected property to the claimed product, as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the engineered immune cell defective for SOCS1 were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
By definition, and per natural law of biology, the T cell is necessarily autologous to the subject from which it was obtained.
10. Claim 24 is 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 17 recites an engineered immune cell defective for SOCS1 and FAS.
Claim 24, dependent upon Claim 17, recites wherein the SOCS1 and FAS activity and/or expression is selectively inhibited or blocked in said engineered immune cell.
Claim 24 fails to further limit the independent claim because the specification discloses that “defective” refers to inhibition or blockade (e.g. pg 13, lines 29-31).
Thus, while Claim 24 recites different words that Claim 17, it encompasses the same result.
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
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.
11. The prior rejection of Claim(s) 17, 20-24, and 29-30 under 35 U.S.C. 102(a)(1) as being anticipated by Hildebrand et al (Frontiers in Immunology 10: e1279, 12 pages, doi: 10.3389/fimmu.2019.01279; available online June 3, 2019; of record) is withdrawn in light of Applicant’s amendment to independent Claims 17 and 29 to recite that the engineered immune cell is defective for both SOCS1 and FAS, a limitation Hildebrand et al do not teach.
12. The prior rejection of Claim(s) 17, 20-24, and 29-31 under 35 U.S.C. 102(a)(1) as being anticipated by Shifrut et al (Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function, Cell 175: 1958-1971, December 13, 2018; of record in specification) is withdrawn in light of Applicant’s amendment to independent Claims 17 and 29 to recite that the engineered immune cell is defective for both SOCS1 and FAS, a limitation Shifrut et al do not teach.
13. The prior rejection of Claim(s) 29-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dotti et al (Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis, Blood 105(12): 4677-4684, 2005) is withdrawn in light of Applicant’s amendment to independent Claims 17 and 29 to recite that the engineered immune cell is defective for both SOCS1 and FAS, a limitation Dotti et al do not teach.
14. The prior rejection of Claim(s) 29-31 under 35 U.S.C. 102(a)(1) as being anticipated by Ren et al (A versatile system for rapid multiplex genome-edited CAR T cells, Oncotarget 8(10): 17002-17011, 2017; of record in IDS) is withdrawn in light of Applicant’s amendment to independent Claims 17 and 29 to recite that the engineered immune cell is defective for both SOCS1 and FAS, a limitation Ren et al do not teach.
15. Claim(s) 17, 20-24, 29-30, and 32-33 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Basar et al (U.S. 2022/0031749; priority to November 28, 2018), as evidenced by SOCS1 Gene Card (www.genecards.org; last visited March 18, 2026).
With respect to Claims 17, 24, and 29-30, Basar et al is considered relevant prior art for having disclosed a method of producing a genetically engineered immune cell, the method comprising the step of contacting the immune cell with an agent that inhibits the expression and/or activity of Fas (syn. CD95) and/or SOCS1 (syn. CISH, CIS-1) (e.g. [0071, 98]; Table 1; claims 1, “the at least two genes are selected from…”, 95, and 122), to wit, CRISPR/Cas9 gene editing system (e.g. [0005, 9, 98]; Table 1; claims 2 and 6-7).
Basar et al do not disclose a reduction to practice of a genetically engineered immune cell in which the expression and/or activity of Fas and SOCS1 are defective.
However, the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970).
Basar et al disclosed that the CRISPR/Cas9 system mediates efficient gene editing of multiple genes, e.g. SOCS1 (syn. CISH) in addition to three other genes (e.g. [0032]), Figures 1-2, “Multiplex Knockout”).
A reference contains an "enabling disclosure" if the public was in possession of the claimed invention before the date of invention. "Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
Thus, no undue experimentation is required.
With respect to Claims 20-21, Basar et al disclosed wherein the engineered immune cell is a T cell, e.g. a CD4+ or CD8+ T cell (e.g. [0008]; claim 25, 71, 101).
With respect to Claims 22-23, Basar et al disclosed wherein the immune cell is isolated from a subject (syn. autologous), including the subject who is to be treated with said genetically modified immune cells (e.g. [0109], “isolating cells from the subject”; claims 26, 72, and 109, “autologous to the subject”), wherein said subject has a cancer (e.g. [0232], “to treat cancer”; claims 105-106, and 111).
With respect to Claims 32-33, Basar et al disclosed a method of treating cancer in a subject, the method comprising the step of administering to said subject at least one genetically engineered immune cell according to Claim 17 (e.g. [0109], “isolating cells from the subject”; claims 26, 72, and 109, “autologous to the subject”), wherein said subject has a cancer (e.g. [0231-232], “to treat cancer”; claims 105-106, and 111). Those of ordinary skill in the art immediately recognize that it is axiomatic and natural law of biology that the engineered immune cells autologous to the subject being treated are ‘allogeneic’.
Thus, Basar et al anticipate the claims.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
16. The prior rejection of Claims 17, 20-24, and 29-33 under AIA 35 U.S.C. 103 as being unpatentable over Shifrut et al (Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function, Cell 175: 1958-1971, December 13, 2018; of record in specification), as applied to Claims 17, 20-24, and 29-31 above, and in further view of Marson et al (WO 2020/014235; filed July 9, 2019; co-authors to Shifrut et al; of record in IDS) is withdrawn for reasons discussed above.
17. Claims 17, 20-24, 29-30, and 32-33 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Shifrut et al (Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function, Cell 175: 1958-1971, December 13, 2018; of record in specification) in view of Marson et al (WO 2020/014235; filed July 9, 2019; co-authors to Shifrut et al; of record in IDS), Ren et al (a versatile system for rapid multiplex genome-edited CAR T cells, Oncotarget 8(10): 17002-17011, 2017; of record in IDS), and Frost et al (U.S. 2017/0356010; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 17 and 29, Shifrut et al is considered relevant prior art for having taught an engineered immune cell, e.g. T cells, genetically modified using the CRISPR/Cas9 gene editing system to disrupt the SOCS1 gene (e.g. pg 1966, col. 1, “CRISPR-ablation of…SOCS1”).
Similarly, Marson et al is considered relevant prior art for having disclosed an engineered immune cell, e.g. T cells, genetically modified using the CRISPR/Cas9 gene editing system to disrupt the SOCS1 gene (e.g. [0113], CRISPR-ablation of SOCS1), wherein said genetically engineered T cells are used in a method of treating cancer in a subject (e.g. Abstract; [0010]). Marson et al disclosed wherein the T cells are obtained from a subject that has cancer, are genetically modified, and then reintroduced into the subject (syn. autologous) [0083].
Neither Shifrut et al nor Marson et al teach/disclose wherein the immune cells genetically engineered to inhibit expression and/or activity of SOCS1 are further engineered to inhibit expression and/or activity of Fas (syn. CD95).
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 17, 29-30, and 32, Ren et al is considered relevant prior art for having taught an immune cell genetically engineered to inhibit expression and/or activity of Fas, alone (e.g. pg 17004-17005) and/or with inhibiting the expression of PD1 and CTLA-4, thereby resulting in an inhibitory pathway-resistant universal T cell (e.g. pg 17003, col. 1). Ren et al taught a xenograft animal cancer model system, wherein the genetically modified T cells are administered to the mouse animal subject (e.g. pg 17009, col. 1, Methods, Mouse xenograft studies).
Ren et al taught that those of ordinary skill in the art previously recognized that ablating Fas (syn. CD95) would lead to an enhancement in T cell function (e.g. pg 17003, col. 1). Ren et al taught that the Fas-negative T cells exhibited a reduction of apoptosis when repeatedly challenged with target cells, leading to increased T cell expansion and reduced activation-induced cell death (AICD) (e.g. pg 17004, col. 2).
Frost et al is considered relevant prior art for having disclosed immune cells genetically modified to inhibit expression and/or activity of SOCS1 and PD1 (e.g. [0009, 199, 502, 572]). Frost et al disclosed wherein inhibition of SOCS1 and PD1 expression and/or activity is lymphoproliferative to induce proliferation of the T cells (e.g. [0188], lymphoproliferative element; [0199]; [0121], as SOCS1 is an art-recognized negative regulator of T cell activation [0201] and PD1 is recognized in the art to function to prevent activation of T cells [0205], and the inhibition of SOCS1 and/or PD1 expression and/or activity prevents T cell inactivation [0121].
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, immunology, and gene silencing and/or gene editing techniques. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to modify the immune cells of Shifrut et al and/or Marson et al comprising a genetic modification that inhibits the expression and/or activity of SOCS1 to further comprise a genetic modification that inhibits the expression and/or activity of Fas (syn. CD95) with a reasonable expectation of success and motivation because:
i) Ren et al taught an immune cell genetically engineered to inhibit expression and/or activity of Fas, alone and/or with inhibiting the expression of PD1, thereby resulting in an inhibitory pathway-resistant universal T cell, whereby those of ordinary skill in the art previously recognized that ablating Fas (syn. CD95) would lead to an enhancement in T cell function, and that the Fas-negative T cells exhibited a reduction of apoptosis when repeatedly challenged with target cells, leading to increased T cell expansion and reduced activation-induced cell death (AICD); and
ii) Frost et al disclosed immune cells genetically modified to inhibit expression and/or activity of SOCS1 and PD1, whereby inhibition of SOCS1 and PD1 expression and/or activity is lymphproliferative to induce proliferation of the T cells, as SOCS1 is an art-recognized negative regulator of T cell activation and PD1 is recognized in the art to function to prevent activation of T cells, and the inhibition of SOCS1 and/or PD1 expression and/or activity prevents T cell inactivation.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a genetic modification that inhibits the expression and/or activity of PD1, as taught by Ren et al, with a genetic modification that inhibits the expression and/or activity of SOCS1, as taught/disclosed by Shifrut et al, Marson et al, and/or Frost et al, in an immune cell genetically engineered to comprise a genetic modification that inhibits the expression and/or activity of Fas (syn. CD95), with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a genetic modification that inhibits the expression and/or activity of PD1 with a genetic modification that inhibits the expression and/or activity of SOCS1 in an immune cell genetically engineered to comprise a genetic modification that inhibits the expression and/or activity of Fas (syn. CD95) because Frost et al disclosed immune cells genetically modified to inhibit expression and/or activity of SOCS1 and/or PD1, whereby inhibition of SOCS1 and/or PD1 expression and/or activity is lymphoproliferative to induce proliferation of the T cells, as SOCS1 is an art-recognized negative regulator of T cell activation and PD1 is recognized in the art to function to prevent activation of T cells, and the inhibition of SOCS1 and/or PD1 expression and/or activity prevents T cell inactivation.
Those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) SOCS1 expression and/or activity behaves as a negative regulator of T cell function, being an art-recognized T cell inhibitory gene (Shifrut et al; Marson et al);
ii) T cells genetically modified using the CRISPR/Cas9 gene editing system to disrupt the SOCS1 gene had been successfully reduced to practice (Shifrut et al; Marson et al);
iii) T cells genetically modified using the CRISPR/Cas9 gene editing system to disrupt at least three target genes, including FAS and PD1, had been successfully reduced to practice, thereby enhancing CAR T cell function (Ren et al); and
iv) Marson et al disclosed said T cells genetically modified using the CRISPR/Cas9 gene editing system to disrupt the SOCS1 gene may be used in methods of treating cancer in a subject, whereby the patient’s own T cells are genetically modified and then reintroduced back into the patient (e.g. [0083]), as inactivation of the negative regulator boosts T cell function (e.g. [0105]), e.g. significantly increased tumor cell clearance (e.g. [0113]).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 20-21, Shifrut et al taught isolating primary immune cells comprising CD8+ T cells (e.g. Supplemental Methods).
Marson et al disclosed isolating primary immune cells comprising CD8+ T cells [0123].
Ren et al taught isolating human primary immune cells comprising CD4+ and CD8+ T cells (e.g. pg 17007, col. 2, Methods, Primary huma lymphocytes).
Frost et al disclosed wherein the immune cell is a CD4+ T cell (e.g. [0418]).
With respect to Claims 22-23, as discussed above, instant claims fail to further limit the independent claim. See 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, rejections above.
Nevertheless, Shifrut et al taught isolating primary immune cells from a subject (e.g. Figure 1a).
Marson et al disclosed wherein the T cells are obtained from a subject that has cancer, are genetically modified, and then reintroduced into the subject (syn. autologous) [0083].
Frost et al disclosed wherein the immune cells are autologous or allogeneic (e.g. [0124]).
With respective to Claims 24 and 30, Shifrut et al taught an engineered immune cell, e.g. T cells, the CRISPR/Cas9 gene editing system to disrupt the SOCS1 gene (e.g. pg 1966, col. 1, “CRISPR-ablation of…SOCS1”).
Marson et al disclosed an engineered immune cell, e.g. T cells, the CRISPR/Cas9 gene editing system to disrupt the SOCS1 gene (e.g. pg 1966, col. 1, “CRISPR-ablation of…SOCS1”).
Ren et al taught the CRISPR/Cas9 gene editing system to disrupt the FAS gene (e.g. Abstract; pg 17003, col. 2, “efficient gene ablation…by targeting….Fas”).
Frost et al disclosed immune cells genetically modified to inhibit expression and/or activity of SOCS1 and PD1 (e.g. [0009, 199]).
With respect to Claim 29, Shifrut et al taught a method of producing a genetically engineered immune cell, the method comprising the step of contacting the immune cell with an agent that inhibits the expression and/or activity of SOCS1, to wit, the CRISPR/Cas9 gene editing system to disrupt the SOCS1 gene (e.g. pg 1966, col. 1, “CRISPR-ablation of…SOCS1”).
Marson et al disclosed an engineered immune cell, e.g. T cells, genetically modified using the CRISPR/Cas9 gene editing system to disrupt the SOCS1 gene (e.g. [0113], CRISPR-ablation of SOCS1), wherein said genetically engineered T cells are used in a method of treating cancer in a subject (e.g. Abstract; [0010]).
Ren et al taught the CRISPR/Cas9 gene editing system to disrupt the FAS gene (e.g. Abstract; pg 17003, col. 2, “efficient gene ablation…by targeting….Fas”).
Frost et al disclosed the method comprising the step of contacting the immune cell with an agent that inhibits the expression and/or activity of SOCS1 or PD1, to wit, inhibitory RNAs such as miRNA or shRNA [0312, 314].
With respect to Claim 32, Marson et al is considered relevant prior art for having disclosed an engineered immune cell, e.g. T cells, genetically modified using the CRISPR/Cas9 gene editing system to disrupt the SOCS1 gene (e.g. [0113], CRISPR-ablation of SOCS1), wherein said genetically engineered T cells are used in a method of treating cancer in a subject (e.g. Abstract; [0010]). Marson et al disclosed wherein the T cells are obtained from a subject that has cancer, are genetically modified, and then reintroduced into the subject (syn. autologous) [0083].
Ren et al taught a xenograft animal cancer model system, wherein the genetically modified T cells are administered to the mouse animal subject (e.g. pg 17009, col. 1, Methods, Mouse xenograft studies).
With respect to Claim 33, Marson et al disclosed wherein the T cells are obtained from a subject that has cancer, are genetically modified, and then reintroduced into the subject (syn. autologous) [0083].
Ren et al taught a xenograft animal cancer model system, wherein the genetically modified T cells are administered to the mouse animal subject (e.g. pg 17009, col. 1, Methods, Mouse xenograft studies).
Frost et al disclosed wherein the immune cells are autologous or allogeneic (e.g. [0124]).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that the cited prior art does not suggest the dual inactivation of both SOCS1 and FAS in the same engineered immune cell.
Applicant’s argument(s) has been fully considered, but is not persuasive.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Applicant argues that there is no reasonable expectation of success for the dual inactivation of both SOCS1 and FAS in the same engineered immune cell.
Applicant’s argument(s) has been fully considered, but is not persuasive. Ren et al taught “triple gene disruption” using the CRISPR/Cas9 system (e.g. Abstract). See also Basar et al. Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art had successfully reduced to practice multiplex gene editing using the CRISPR/Cas9 system, and thus would have had a reasonable expectation of success for the dual inactivation of both SOCS1 and FAS in the same engineered immune cell.
Applicant provides no objective evidence to the contrary.
Applicant argues secondary consideration that the dual inactivation of both SOCS1 and FAS in the same engineered immune cell significantly improved results, as compared to inactivation of FAS alone (e.g. Figure 7d-e, g-h).
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, instant independent Claim 32 merely requires the administration of just one(!) engineered immune cell (generic); whereas, Applicant’s asserted secondary consideration was achieved via administration of at least 2x10^6 engineered T cells (e.g. pg 64, Figure 7 description). Those of ordinary skill in the art would immediately recognize that instant Claim 32 is simply not commensurate in scope to the asserted secondary consideration.
As a second matter, Ren et al taught that the generation of T cells resistant to multiple inhibitory pathways is “expected to improve the function of CAR T cell therapy” (e.g. pg 170002, col. 2).
Conclusion
18. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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