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 .
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 07/01/2026 is acknowledged. The traversal is on the grounds that the claims present unity of invention. This is not found persuasive because, even if, in arguendo, one considers Applicant remarks to be valid, the claims are drawn to more than one product and a process of use. Another ground of travers was that restriction between claim 1 and its dependent claims is improper. This argument was found partially valid and some claims will be rejoined for further examination. Nevertheless, the claims drawn to CAR and/or engager were not rejoined since they describe a different product, since, according to claim 1, their presence is optional. Upon further consideration, the election of species requirement is withdrawn. Claims 1-52 are pending; claims 7, 8, 25, and 32-52 are withdrawn from prosecution as being drawn to non-elected subject matter. Claims 1-6, 9-24 and 26-31 are examined.
The requirement is still deemed proper and is therefore made FINAL.
Claim Rejections - 35 USC § 112
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 1-6, 9-24 and 26-31 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.
There are multiple issues regarding the claims being rendered indefinite:
The wording “optionally” render the claims 1,2, 12, 19, 24, 28 and 29 as indefinite since it is not clear if the limitation following the word is to be conserved as a limitation or not. As such the metes of the claims (and of their dependent claims) could not be determined.
The claiming of limitations with the aid of “Table NO” renders the claim indefinite: "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table 'is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)). There is no limit to the length of a claim. If the subject matter can be listed in the specification, that list can be copied and pasted into a claim.
The words: "partial peptide", “partial ectodomain" or “partial length” render the claims 9, 10, 12, 28, 29 (and their dependents) indefinite because is unclear what kind of partial structure is included.
The words: “functional variant", "variant thereof", "functional equivalents and biosimilar thereof", render claims 9,12,13, 22, 24, 25, 28 and 29 (and their dependents) indefinite because is unclear what specific compounds the above-mentioned variants, fragments, functional equivalents, and biosimilar include.
In claim 10, the limitation “F176V and S197P” is indefinite because the numbers, absent a denomination of a SEQ ID NO:, are meaningless.
Claim 22 recites: "feeder cell" and "feeder cell component or its replenishing
factor", but it is unclear what kind of cell it specifically means, and what kind of
component or replenishing factor it means.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 9-24 and 26-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). (emphasis added). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 (“[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims.”). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity.
Lastly, even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
The claims are drawn to a cell or a population thereof, wherein the cell is an eukaryotic cell, an animal cell, a human cell, an immune cell, an induced pluripotent cell (iPSC), a clonal iPSC or a derivative cell differentiated therefrom, and wherein the cell comprises:
(i) an exogenous polynucleotide encoding a transgenic TCRα chain (tgTCRα);
and
(ii) an exogenous polynucleotide encoding a transgenic TCRβ chain (tgTCRβ),
wherein (a) the tgTCRα chain and the tgTCRβ chain form an exogenous TCR
complex (TCRexo) that recognizes a first tumor antigen and (b) the first tumor
antigen comprises MRI or NYESO1 and optionally,
(iii) one or more additional exogenous polynucleotides comprising a
polynucleotide encoding a chimeric antigen receptor (CAR) or an engager
targeting at least a second tumor antigen. The polynucleotide encoding the tgTCRα chain and the polynucleotide encoding the tgTCRβ chain are comprised in a bi-cistronic construct. The cell further comprises one or more of:
(i) CD38 knockout;
(ii) HLA-1 deficiency and/or HLA-11 deficiency;
(iii) introduced HLA-G or non-cleavable HLA-G, or knockout of one or both of
CD58 and CD54;
(iv) a CD16 or a variant thereof;
(v) a chimeric fusion receptor (CFR);
(vi) a signaling complex comprising a partial or full peptide of a cell surface
expressed exogenous cytokine and/or a receptor thereof;
(vii) at least one of the genotypes listed in Table I;
(viii) deletion or disruption of at least one ofB2M, CIITA, TAPI, TAP2, Tapasin,
NLRC5, RFXANK, RFX5, RFXAP, TCR, NKG2A, NKG2D, CD25, CD69, CD44, CD56, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT; or
(ix) introduction or upregulation of at least one of HLA-E, 4-lBBL, CD3, CD4,
CD8, CD16, CD47, CDl 13, CD13 l, CD137, CD80, PDL1, A2AR, Fc receptor,
an antibody or functional variant or fragment thereof, a checkpoint inhibitor,
and surface triggering receptor for coupling with an agonist.
The cell has therapeutic properties comprising one or more of:
(i) increased cytotoxicity;
(ii) improved persistency and/or survival;
(iii) enhanced ability in migrating, and/or activating or recruiting bystander
immune cells, to tumor sites;
(iv) improved tumor penetration;
(v) enhanced ability to reduce tumor immunosuppression;
(vi) improved ability in rescuing tumor antigen escape;
(vii) controlled apoptosis;
(viii) enhanced or acquired ADCC; and
(ix) ability to avoid fratricide,
in comparison to its counterpart primary cell obtained from peripheral blood,
umbilical cord blood, or any other donor tissues without the same genetic edit(s).
The cell comprises one of the genotypes listed in Table 1; or comprises:
(i) (1) a CD19-CAR at TRAC locus, (2) a TRAC knockout, and (3) a MR1-TCR or a NYESO1-TCR, and optionally (4) a TRBC knockout;
(ii) (1) a BCMA-CAR and hnCD16 insertion at TRAC locus, (2) a TRAC knockout,
and (3) a MR1-TCR or NYESO1-TCR, and optionally (4) a TRBC knockout; or
(iii) (1) a MICA/B-CAR insertion at TRAC locus, (2) a TRAC knockout, (3) a
hnCD16 insertion at CD38 locus, (4) a CD38 knockout, and (5) a MR1-TCR or NYESO1-TCR, and (6) a TRBC knockout.
For this enormous genus claimed, in the examples of the Specification, an MR1 cloned T cell receptor (TCR) construct is transduced into an iPSC (TiPSC) (CAR /TCR-TiPSC) reprogrammed from T cells containing CAR at the TRAC locus or transduced into fibroblasts into reprogrammed iPSC (FiPSC); MR1-TCR can stabilize surface expression of CD3 molecules in effector cells that are negative for endogenous TCR expression, including T cells with TCR α knockout and FiPSC derived T lineage cells (example 2); effector cells expressing MR1-TCR exhibit MR1-TCR-dependent killing capacity against cancer cells (example 3); effector cells expressing MR1-TCR are compatible with BiTE targeting (example 4); further TRBC knockout in TiPSC corrects mispairing and improves exogenous TCR function (example 5); MR1 clone T cell receptor (MR1-TCR) and high affinity non-cleavable CD16 Fc receptor (hnCD) are used to combine potent chimeric antigen receptor (CAR) targeting therapy with universal targeting of secondary and tertiary antigens. An exemplary MR1 clonal T cell receptor (MR1-TCR) and a high-affinity non-cleavable CD16 Fc receptor (hnCD16) were expressed in iPSC-derived CAR19 T cells (CAR19-iT cells) or iPSC-derived CAR-BCMA T cells (CAR-BCMA iT cells) directed to leukemia and lymphoma, and in CAR-MICAS T cells directed to solid tumors (example 6). The expression of exogenous TCR enhances CAR-induced tumor killing efficacy even in the absence of activation by TCR ligands (example 7). The compatibility and enhanced functionalities between CAR, TCR, and CD16-mediated ADCC in mitigating tumor escape resulting from tumor heterogeneity by both in vitro and in vivo tumor models have been demonstrated, providing off-the-shelf cellular immunotherapeutic strategies in dealing with heterogeneous and difficult-to-treat solid tumors (example 8). This represent the extent of what Applicant was in possession of. However, the genus claimed is extremely large and the few examples presented would not conduce an ordinary skilled artisan to consider that they represent a representative number of species for the genus claims and thus Applicant is not in possession of the genus claimed but only the species presented in the examples of the Specification.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Shi et al. (CN108456247A) The invention discloses a NY-ES0-1-targeting T cell receptor and uses thereof, wherein the NY-ESO -1-targeting T cell receptor is formed by linking a NY-ESO-1TCR(alpha) chain, P2A and a NY-ESO-1 TCR(beta) chain in series. According to the present invention, the T cell receptor is used for modifying human T lymphocytes, and the modified T cells (TCR-T cells) can be used for the treatment of HLA-A2+NY-ESO-1 positive tumors: and the prepared NY-ESO-1 TCR-T cells have strong functions on specific tumor cells (U266 and T2-NY-ES0-1 ), has high CD107a expression and high IFN[gamma] secretion, and achieves the killing efficiency of 80% in the case of an effect-to-target ratio of 5:1 (abstract).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLY GERALD STOICA whose telephone number is (571)272-9941. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ELLY-GERALD STOICA
Primary Examiner
Art Unit 1647
/Elly-Gerald Stoica/Primary Examiner, Art Unit 1647
Prosecution Insights