DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed on September 11, 2024 is pending.
Claims 1-107 are canceled.
Claims 108-110 are pending and currently under consideration.
Priority
The present application is CON of abandoned Application No.16/371,501 filed on 04/01/2019 which is a CON of Application No. 15/551,862 filed on 08/17/2017, now U.S. Patent No. 10,273,280, which is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2016/019953, filed 02/26/2016. This application is claiming the benefit under 35 U.S.C. 119(e) of prior-filed U.S. Provisional 62/121,842 filed on 02/27/2015.
A certified copy of PCT/US2016/019953 (WO 2016/138491) has been filed on 8/17/2017 with the parent application serial number 15/551,862 (now U.S. Patent 10,273,280).
Claim Rejections - 35 USC § 112
Written Description
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 108-110 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 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.
The instant claims are drawn to a method of treating T-cell acute lymphoblastic leukemia (T-ALL) or peripheral T-cell lymphoma in a patient in need thereof wherein said method comprises administering to said patient an engineered cell expressing a polypeptide comprising a chimeric antigen receptor polypeptide (CAR), where the CAR comprises a signal peptide, an antigen recognition domain, a hinge region, a transmembrane domain, at least one co-stimulatory domain, and a signaling domain and wherein the antigen recognition domain is selective for CD7.
To support such anti-CD7 CARs that are to be applied in the method recited in the preamble of claim 108, the Applicant discloses a single species which includes the amino acid sequence of SEQ ID NO: 17 (e.g. see page 25, line 16 of the instant specification).
When given the broadest reasonable interpretation in light of specification, the anti-CD7 CARs of the instant invention are defined broadly to be any CAR molecule that comprises an anti-CD7 antigen binding domain.
It is noted that the broadest claim (claim 108) does not indicate any specific structure for the genus of anti-CD7 CARs claimed.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
It is well known that antigen binding domains of CARs fall in three general categories, either single chain variable fragments (scFvs) derived from antibodies, Fab’s selected from libraries, or natural ligands that engage their cognate receptor (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”). Successful examples in each of these categories–too many to cite–have been reported. scFvs derived from murine immunoglobulins are commonly used, as they are easily derived from well-characterized monoclonal antibodies. They however may prove to be more immunogenic than Fab’s derived from human libraries or invariant human ligands (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”).
Regarding CARs comprising antibody-derived antigen binding domains, artisans are well aware that knowledge of a given antigen (for instance CD7) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
As noted above, the specification only discloses a single species of anti-CD7 CAR which includes the amino acid sequence of SEQ ID NO: 17. Such a disclosure does not serve to provide sufficient written description of the claimed genus of polypeptide complexes. Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of binding to CD7. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited anti-CD7 CARs which gives rise to their functional activity. As such, the instant specification appears to disclose applicant’s wish for CARs that bind to CD7 without informing artisans what such CARs actually are.
Ultimately, identifying an antibody simply on the basis of what it binds rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide written description of the antibody in question.
Regarding species of anti-CD7 CARs that comprise ligands that engage their cognate receptor instead of antibodies or fragments thereof as the antigen binding domain, the same logic above applies: structure does not necessarily correlate with function. Anti-CD7 CARs comprise antigen-binding ligands still require very precise structure in order confer binding function.
Ultimately, there is insufficient written description for the breadth anti-CD7 CARs as currently claimed, which are distinct and diverse (e.g. antibodies or functional fragments thereof, or ligands) and do not share a common structure that contributes to a common ability to bind to CD7. One of ordinary skill in the art cannot envision from the disclosed species provided (i.e., SEQ ID NO: 17), the entire genus of anti-CD7 CARs of the instant invention.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of anti-CD7 CARs encompassed by the claims at the time the instant application was filed.
Enablement
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 108-110 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for T-cell acute lymphoblastic leukemia (T-ALL), does not reasonably provide enablement for any peripheral T-cell lymphoma. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors considered in determining whether a disclosure would require undue experimentation include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP § 2164.01.
The instant specification does not reasonably provide enablement for a method of treating any peripheral T-cell lymphoma in a patient in need thereof by administering an engineered cell expressing an anti-CD7 CAR.
Nature of the invention/Breadth of the claims
Independent claim 108 is drawn to a method of treating T-cell acute lymphoblastic leukemia (T-ALL) or any peripheral T-cell lymphoma in a patient in need thereof by administering an engineered cell expressing an anti-CD7 CAR.
Dependent claim 109 is drawn to the method wherein the engineered cell is a T or NK cell.
Dependent claim 110 is drawn to the method wherein the engineered cell is administered in conjunction with radiation therapy, hormone therapy, chemotherapy, checkpoint inhibitor, immunotherapy or a combination thereof.
State of the prior art/Predictability of the art
Gomes-Silva et al. 2017 (Blood. 130(3); 285-296), Xie et al. 2020 (Exp Hematol Oncol. 9(30): 1-15), and Yang et al. 2024 (Blood. 144(Supplement 1); 2075-2076) all teach that CD7, a transmembrane protein highly expressed in acute T-cell leukemia (T-ALL), is only expressed in a subset of peripheral T-cell lymphomas (PTCL) (e.g. see Gomes-Silva et al. Abstract and paragraph spanning pages 285 and 286; Xie et al. page 10, right column, second paragraph; and Yang et al. page 2075, second paragraph under “Introduction”). However, frequent loss of CD7 is observed in tumor cells of PTCL (e.g. see Xie et al. page 10, right column, second paragraph).
Vonderheid et al. 2001 (J Invest Dermatol. 117(3); 654-662) further demonstrate the differential expression of CD7 in PTCL. Specifically, Vonderheid et al. teach that CD7 expression on malignant T cells varies widely among cases of leukemic CTCL, a type of PTCL, and that CD7 expression by cells does not clearly segregate into two distinct subgroups that are either CD7 positive or CD7 negative as generally thought (e.g. see page 660, left column, first paragraph). In fact, roughly half of patients analyzed by Vonderheid et al. with a predominantly CD4+CD7+ tumor population on early studies became CD4+CD7‒ over time whereas the converse situation was not observed (e.g. see Abstract). This observation is similar to that taught by Xie et al. as recited above.
Regarding the application of anti-CD7 CAR-expressing cells for treating PTCL, Xie et al. and Yang et al. teach that CD7-specific CAR-expressing cell therapy is restricted to patients with CD7-expressing cancers (e.g. see Xie et al. page 10, right column, second paragraph; and Yang et al. page 2075, paragraph under “Methods”).
Yang et al. specifically teach that PTCL encompass a broad class of heterogeneous clinicopathologic entities unified in their derivation from a mature, post-thymic T-cell (e.g. see page 2075, first paragraph under “Introduction”). For patients with relapsed or refractory (R/R) PTCL, outcomes are generally poor, even with an allogeneic hematopoietic stem cell transplantation (allo-HSCT), creating a great need of new therapeutics (e.g. see page 2075, second paragraph under “Introduction”). Yang et al. have previously demonstrated that “naturally selected” CD7 CAR-T (NS7CAR-T) therapy shows significant efficacy with a favorable safety profile in 60 patients with T-ALL and T-cell lymphoblastic lymphoma (T-LBL) (e.g. see page 2075, second paragraph under “Introduction”).
Yang et al. further demonstrated that CD7-positive heavy pre-treated R/R PTCL patients could achieve a promising complete response (CR) and safety profile after CD7-targeted CAR-T therapy, who otherwise have very limited therapy options (e.g. see page 2076, paragraph under “Conclusions”). It is noted that only patients who were diagnosed with r/r PTCL and had positive CD7 expression were eligible (e.g. see page 2075, paragraph under “Methods”). It is further noted that Yang et al. acknowledged that more data on additional patients and longer observation times are needed to further evaluate the efficacy and safety of CD7 CAR-T products in treating PTCL (e.g. see page 2076, paragraph under “Conclusions”).
Taken together, the art ultimately teaches that anti-CD7 CAR T cell therapy is only applicable to those patients whose cancer expresses CD7. The art further, and arguably, more importantly, teaches that CD7 expression: (1) is not found in every type of PTCL; (2) can be lost over time in some patients; (3) varies wildly even among specific subsets of PTCL.
Thus, it would be unpredictable to one of ordinary skill in the art to use the an anti-CD7 CAR-expressing cell to treat any PTCL as encompassed by the breadth of the claims.
Working examples/Guidance in the specification
While the specification does provide an example of using an anti-CD7 CAR NK cell to treat T-ALL (e.g. see page 77, line 25- page 78, line 5, and Figure 43), it does not provide any working examples for treating PTCL with an anti-CD7 CAR T cell.
In fact, the specification teaches that CD7 is expressed on the surface of mature T cells and is the earliest surface antigen expressed on T cell lineage cells (e.g. see page 38, lines 8-13). The specification further teaches that CD7 is a very good marker for T-ALL (more than 90% of T-ALL express CD7) and that CD7 is also expressed in NK lymphoma, T cell lymphoma/leukemia, chronic myeloid leukemia, acute myeloid leukemia, and lymphocyte rich thymoma (e.g. see page 38, lines 8-13).
Together, the examples disclosed by the Applicant and guidance provided by the specification do not teach one of ordinary skill in the art to use the an anti-CD7 CAR-expressing cell to treat PTCL.
Amount of experimentation necessary
The instant specification discloses only one example of anti-CD7 CAR therapy and it is specific for T-ALL, not PTCL, yet, the claims are not limited to the use of an anti-CD7 CAR-expressing cell in treating T-ALL. The claimed methods encompass administering an anti-CD7 CAR-expressing cell to patients in need thereof for treating T-ALL or any PTCL. There is insufficient objective evidence that the disclosed method of treating T-ALL with an anti-CD7 CAR-expressing cell can be extrapolated to provide guidance and direction for the claimed method of treating any PTCL by administering these cells.
Thus, based on the content of the disclosure in view of the prior art regarding the varied expression of CD7 in PTCL, a skilled artisan, through extensive trial-and-error experimentation, would have to identify the specific subsets PTCL that express CD7 and then use an anti-CD7 CAR-expressing cell to treat the identified PTCL with a reasonable expectation of success. This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method for the breadth of what is claimed.
Given that anti-CD7 CAR T cell therapy is only applicable in CD7-expressing cancers and that CD7 expression: (1) is not found in every type of PTCL; (2) can be lost over time in some patients; (3) varies wildly even among specific subsets of PTCL; a person having ordinary skill in the art would have to perform undue experimentation in order to use an anti-CD7 CAR-expressing cell commensurate in scope with the breadth of the claims.
Thus, the specification does not enable one of ordinary skill in the art to use what is claimed and therefore claims 108-110 are rejected under 35 U.S.C. 112(a).
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.
Claim 108-110 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fedorov and Sadelain 2014 (CA 2904265 A1).
Fedorov and Sadelain teach methods of using immunoresponsive cells, such as T cells or Natural Killer (NK) cells, which express an antigen binding receptor, such as a CAR, having immune cell activating activity, and an inhibitory CAR (iCAR) that selectively reduces or eliminates the immune activity of the immunoresponsive cell for the treatment of neoplasia (e.g. see page 2, lines 19-27). Such neoplasias include acute lymphoblastic leukemia (ALL) (e.g. see page 3, lines 13-15). Fedorov and Sadelain specifically teach that their antigen recognizing receptor may bind a tumor antigen, such as CD7 (e.g. see page 5, lines 3-7).
Fedorov and Sadelain define a CAR as an antigen-binding domain that is fused to an intracellular signaling domain capable of activating or stimulating an immune cell. Most commonly, the CAR's extracellular binding domain is composed of a single chain variable fragment (scFv) (e.g. see page 8, lines 13-16). The scFv is fused to a transmembrane domain and then to an intracellular signaling domain and may further include one or more costimulatory domains, such as CD28 or CD137 (e.g. see page 8, lines 20-25).
Regarding the limitation of the CAR also comprising “a hinge region” in line 5 of claim 108, Fedorov and Sadelain teach that their iCARs may utilize CD8, CD4, or endogenous hinge domains (e.g. see page 58, lines 13-29. Thus while Fedorov and Sadelain do not explicitly teach that their CAR (not iCAR) comprises a hinge region, it well known to skilled artisans that CARs inherently comprise a hinge region. The hinge region is critical for linking the extracellular binding domain to the intracellular signaling domain. Thus, Fedorov and Sadelain’s teaching of an iCAR comprising a hinge can be extrapolated to their anti-CD7 CAR because the anti-CD7 CAR would inherently require a hinge region to connect the CD7 antigen recognition domain with the transmembrane domain and in turn the intracellular components of the CAR.
Regarding the limitation “wherein the engineered cell is administered in conjunction with radiation therapy, hormone therapy, chemotherapy, checkpoint inhibitor, immunotherapy or a combination thereof” recited in lines 1-3 of claim 110, given its broadest reasonable interpretation, the inclusion of the iCAR on the anti-CD7 CAR-expressing immunoresponsive cell constitutes an immunotherapy that is administered in conjunction with the anti-CD7 CAR T-cell.
Conclusion
No claim is allowed.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/CHUN W DAHLE/Primary Examiner, Art Unit 1641