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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 10, 2025 has been entered.
Claim Status
Claims 1, 3, and 5-20 are currently pending in this application.
Election/Restrictions
Election was made without traverse of Group I, claims 1-4, in the reply filed on Dec. 7, 2022, and claims 5-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected subject matter, there being no allowable generic or linking claim. Claims 1 and 3 have been considered on the merits. All arguments have been considered.
Benefit of Priority Claim
Acknowledgement is made of applicant’s claim for the benefit of the prior-filed applications US 62/710,591 and US 62/673,624 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c). The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application US 62/710,591 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for the claims of this application. Entitlement to priority to Feb. 16, 2018 does not apply to the subject matter of claims 1 and 3 (e.g., due to a lack of support for wherein the HLA-E trimer is delivered using AAV6), therefore the earliest effective filing date of claims 1 and 3 is May 18, 2018 based on the filing date of US 62/673,624.
Claim Interpretation
The modified pluripotent stem cell of the claims 1 and 3 is interpreted as engineered to lack endogenous HLA expression via the (ii) deficient b2m gene but only optionally engineered to eliminate endogenous TCR expression, thus clearly falling in elected Group I.
In claim 1, the term “HPV-16 E7 TCR gene” is interpreted to mean a gene encoding a TCR with specificity to a peptide fragment of the protein HPV-16 E6.
In claim 1, the term “single HLA-E trimer” is interpreted to mean any protein comprising exactly three HLA-E components. Further in claim 1, the HLA-E trimer is limited by the phrase “is a fusion of native HLA-E and beta 2 microglobulin (b2m)” which is interpreted to mean the single HLA-E trimer consists of a single polypeptide chain comprising three HLA-E components, each having a naturally occurring HLA-E sequence, and at least one b2m component, whereby the three HLA-E components properly form an HLA-E trimer-like structure, e.g., to provide at least one functional attribute shared with a native HLA-E trimer. In other words, a person of skill in the art could examine the single HLA-E trimer sequence and readily identify three “native” HLA-E sequences known to occur in nature.
In claim 1, the term “FMC63 CD19” with regard to a component of a chimeric antigen receptor (CAR) is interpreted to mean a CD19 specific antigen binding polypeptide moiety which is able to activate an immune cell expressing it to its cell surface upon binding to the antigen via intracellular signaling domain(s) (see instant [0249], [0238]; [0004], [0018]).
In claim 1, the phrase wherein the HPV-16 EV is delivered using adeno associated virus serotype 6 (AAV6) is interpreted as a product-by-process such that there is no recited or implied structural feature(s) that would distinguish the modified pluripotent stem cell comprising an exogenous HPV-16 EV made in this manner from one made by another process, e.g., using AAV2.
In claim 1, the phrase wherein the HLA-E trimer is delivered using AAV6 is interpreted as a product-by-process such that there is no recited or implied structural feature(s) that would distinguish the modified pluripotent stem cell comprising the single HLA-E trimer fusion protein (or exogenous construct encoding said HLA-E trimer) made in this manner from one made by another process, e.g., using AAV2.
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 1 and 3 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 1 recites the term “the HPV-16 EV”, which lacks sufficient antecedent basis. Furthermore, a person of ordinary skill in the art reading the claim would not understand the metes and bounds of an “HPV-16 EV”, which is not defined in the claims or the instant application.
Claim 1 recites the phrase “delivered using” regarding an AAV6 delivering an HLA-E trimer or HPV-16 EV. A person of ordinary skill in the art reading the claim would not understand the metes and bounds of “delivered using” in each phrase, such as delivered to what (e.g., the pluripotent stem cell) and whether the virus is delivering the protein itself or a construct/gene encoding the protein needing to be expressed by a host cell, e.g., the single HLA-E trimer or a TCR. Furthermore, grammatically the phrase delivered using a virus serotype is nonsensical as merely a category of virus, instead the claim should be written to clarify whether to mean delivered using a virus having the AAV6 serotype and/or a viral vector having an AAV6 serotype.
Claim 3 and is included in this rejection due to its dependence from indefinite claim 1.
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 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Crooks (WO 2017075389 A1; IDS ref.) in view of Wiltzius (WO 2017173256 A1), Gornalusse (Gornalusse et al., Nat Biotechnol 35: 765-72 (2017)), Kochenderfer (Kochenderfer et al., Blood 116: 4099-102 (2010)), and Manzo (Manzo et al., Hum Mol Genet 24: R67-73 (2015)).
In claim 1, the term “HPV-16 E7 TCR gene” is interpreted to encompass an exogenous construct encoding a TCR reactive against HPV-16 E7 (see instant [0024], [0016]).
Crooks teaches modifying pluripotent stem cells to comprise (i) an exogenous TCR gene, (iv) an exogenous construct encoding a chimeric antigen receptor (CAR) and a suicide gene and/or selectable marker, wherein the CAR comprises a CD28 costimulatory domain (intracellular domain) and CD3-zeta domains ([0026]; [0044]; [0268]; [0272]-[0274; [0222]-[0224]; [0166]). Crooks teaches using these modified pluripotent stem cells to make immune cells for adoptive cell therapies, such as antigen specific T cells, natural killer cells, and regulatory T cells ([0045]; [0030]). Crooks also teaches genetically modifying the HLA-type of these cells, such as to make allogeneic off-the-shelf cells with respect to potential recipients ([0274]; [0005]), which also lack a risk of causing graft-versus-host disease due to being engineered to be deficient for endogenous TCR ([0270]). Crooks teaches methods for generating antigen-specific TCR genes for a target of interest are known in the prior art, such as to a desired overexpressed tumor-associated antigen ([0197]). Although Crooks does not teach the exogenous TCR construct was delivered using an adenovirus associated virus of serotype 6 (AAV6), as noted in the claim interpretation section, the process phrase “delivered using AAV6” is interpreted as non-limiting for the claimed product.
While Crooks does not teach wherein the suicide gene is specifically a chemically induced caspase, Wiltzius teaches exogenous suicide gene constructs which encode inducible caspase-9 to provide for cell elimination during cell therapy for safety reasons to help minimize adverse events ([0211]). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select the suicide gene for the modified pluripotent stem cell taught by Crooks to be an inducible caspase-9 construct as taught by Wiltzius. One of ordinary skill in the art would be motivated to choose an already validated suicide gene with proven effectiveness and convenience that eliminates engineered cells in a patient simply upon exposure to a small molecule chemical inducer of the inducible caspase-9 (e.g., rimiducid).
Crooks does not teach wherein a pluripotent stem cell comprises (ii) a deficient beta 2 microglobulin (b2m) gene and (iii) an exogenous construct encoding a single HLA-E trimer consisting of a fusion of native HLA-E and b2m or wherein the TCR is specific to an HPV-16 E7 epitope and the CAR is specific to a CD19 antigen.
However Gornalusse teaches a modified pluripotent stem cell comprising a single chain HLA trimer comprising a native HLA-E sequence in triplicate fused to b2m via a linker and comprising fused to the N-terminus an antigen peptide (HLA-G signal) bound in the HLA-E trimer antigen binding pocket for presentation (pg. 765, right col., 2nd full para., to pg. 766, right col.; Fig. 1A-C). Gornalusse teaches that expression of an engineered HLA single-chain trimer in cells having a deficient b2m (B2M) gene prevents allogeneic responses and lysis with the added benefit of not stimulating allogeneic T cells (Abstract, pg. 765, right col., first full para.; pg. 767, right col., last para. to pg. 770, 2nd para., Fig. 3e-f, Fig. 4c-e, Suppl. Fig. 4d-f, Suppl. Fig. 6a-b). Gornalusse teaches that the elimination of endogenous HLA expression by B2M knockout results in the major limitation of lysis by natural killer cells through a ‘missing-self’ response (pg. 765, left col., 2nd para.) but that the combination of B2M disruption and forced surface expression of an HLA single-chain trimer can create an improved source for universal donor cells (Abstract; pg. 765, right col., first full para). Furthermore, Gornalusse teaches wherein the single chain HLA trimer specifically comprises a “native” HLA-E (pg. 765, right col., 2nd full para., to pg. 766, right col.; Fig. 1A-C) fused to B2M and a stabilizing peptide (peptide antigen or HLA-G signal peptide), e.g., “G peptide” (Abstract; Fig. 1a; pg. 765, right col., 3rd para.). Gornalusse teaches that expression of this engineered HLA-E-B2M-G peptide single-chain trimer in cells having a deficient b2m (B2M) gene prevents allogeneic responses and lysis with the added benefit of not stimulating allogeneic T cells (Abstract, pg. 765, right col., first full para.; pg. 767, right col., last para. to pg. 770, 2nd para., Fig. 3e-f, Fig. 4c-e, Suppl. Fig. 4d-f, Suppl. Fig. 6a-b).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify the engineered pluripotent stem cell taught by Crooks and Wiltzius to comprise (ii) a deficient beta 2 microglobulin (b2m) gene and (iii) an exogenous construct encoding a single HLA-E trimer consisting of a fusion of native HLA-E and b2m as taught by Gornalusse. One of ordinary skill in the art with the goal of making off-the-shelf allogeneic cells would be motivated to because Gornalusse teaches the combination of an endogenous b2m knockout with expression of an engineered exogenous single-chain HLA trimer prevents allogeneic responses by not stimulating allogeneic T cells as a way to make improved universal donor cells for adoptive cell therapies. Although Crooks does not teach the pluripotent stem cells comprise the HLA-E trimer encoding construct delivered using an AAV6 virus or vector; as noted in the claim interpretation section, the process phrase “delivered using AAV6” is interpreted as non-limiting.
Although Crooks teaches the TCR is a virus or cancer cell-specific TCR and the CAR binds a tumor antigen ([0063]), Crooks does not teach expressly wherein the TCR is specific to an HPV-16 E7 epitope and the CAR binds to CD19 (i.e., comprises FMC63 CD19). However Kochenderfer teaches an anti-CD19 CAR comprising an FMC63 scFv for use in genetically engineered T cells for treating B-cell cancers (Abstract, pg. 4099, left col., 2nd para.). Kochenderfer teaches this CAR was successfully used to benefit a human lymphoma patient and to eliminate CD19-expressing cells in an antigen-specific manner over a long period by infusion of engineered adoptive T cells expressing this anti-CD19 CAR specifically comprising FMC63 scFv (Abstract; Fig. 1-2; pg. 4101, right col., last para.).
Furthermore Crooks teaches the TCR is a virus or cancer cell-specific TCR ([0063]) and wherein its function of the exogenous TCR is for allelic exclusion during T development and then merely an inert passenger during adoptive cell therapy targeted only by the CAR ([0048]), and Manzo teaches HPV-16 E7 is a viral and carcinoma associated antigen (R69, left col., last para.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing with the goal of treating a B-cell cancer to select CD19 as the CAR target for the modified pluripotent stem cells taught by Crooks, Wiltzius, and Gornalusse wherein the anti-CD19 CAR specifically comprises the FMC63 scFv taught by Kochenderfer. One of ordinary skill in the art would be motivated to use the FMC63 scFv taught by Kochenderfer because it has already been validated in the clinic to provide T cells with CD19 antigen-specific cancer cell depletion function in vivo. One of ordinary skill in the art would be motivated to do all of the aforementioned to make an anti-CD19 CAR-T cell allogeneic adoptive therapy to treat B-cell cancers because Crooks provides off-the-shelf stem cells for differentiation into universal donor T-cells for allogeneic adoptive cell therapies and Kochenderfer teaches using T cells engineered to express an anti-CD19 CAR for treating B-cell malignancies. Further, It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing with the goal of treating a B-cell cancer to select any exogenous TCR in view of Crooks to set the HLA subtype via allelic exclusion during T development and then to merely act as an inert passenger during adoptive cell therapy, such as any desired HLA subtype of a TCR specific to an arbitrary HPV-16 E7 antigen already known in the prior art to make a set of allogeneic off-the-shelf universal donor cells with respect to any pool of HLA-matched recipients.
Regarding claim 3, there is no structural feature(s) recited in the claims that would distinguish a modified pluripotent stem cell made by a particular gene editing process (e.g., using a CRISPR/Cas9, zinc finger nuclease (ZFN), TALEN, MegaTAL, meganuclease, Cpf1, homologous recombination, or single stranded oligodeoxynucleotide (ssODN)) versus one made by any other editing process for creating the claimed product. Thus, the subject matter of claim 3 is obvious in light of Crooks in view of Wiltzius, Gornalusse, Kochenderfer, and Manzo for the same reasons as claim 1 set forth above.
Furthermore, Crooks teaches gene editing pluripotent stem cells using homologous recombination, CRISPR/Cas9 systems, Zinc finger nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and engineered meganuclease re-engineered homing endonucleases, such as to disrupt endogenous genes by knock-in ([0043]; [0228]-[0235]). It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to design the engineered pluripotent stem cell taught by the combination of Crooks, Wiltzius, Gornalusse, Kochenderfer, and Manzo using a CRISPR/Cas9, ZFN, TALEN, meganuclease, and/or homologous recombination as genome editing tools, as well as other equivalent methods already routine in the prior art, such as homologous recombination via homology arms constructs delivered by recombinant AAV to mediate knockout of B2M (null) and/or knockin of the HLA-E trimer encoding construct into the B2M locus, as both are taught by Gornalusse (Fig. 1b).
Thus, the claimed invention as a whole is prima facie obvious before the effective filing date in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed June 20, 2025 have been fully considered and found persuasive. However, Applicant's amendment necessitated the new grounds of rejection presented fully above.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERIC J ROGERS/
Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638