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 .
The amendment filed 1/9/24 is acknowledged. Claims 1-209 have been canceled. Claims 210-225 have been added. Claims 210-225 are pending and under examination.
Specification
The use of the term TexMACS™, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The entire specification should be checked for these kinds of informalities and correction is required.
Claim Rejections - 35 USC § 112
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 210-225 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.
The claims are drawn to method of treating acute myeloid leukemia (AML) in a subject, comprising administering to the subject an effective amount of a composition comprising a plurality of T cells that express a chimeric ligand receptor (CLR) that specifically binds to c-KIT, wherein the CLR comprises:(a) an ectodomain comprising: i) a signal peptide comprising a human CD8α signal peptide; ii) a scFv comprising the amino acid sequence of SEQ ID NO: 73; and iii) a hinge domain comprising a human CD8α hinge domain; (b) a transmembrane domain comprising a human CD8α transmembrane domain; (c) a co-stimulatory domain comprising a human 4-1BB costimulatory domain; and (d) an endodomain comprising a human CD3ζ endodomain.
Although the claims are inclusive of the fully described CLR, wherein the CLR comprises:(a) an ectodomain comprising: i) a signal peptide comprising the amino acid sequence of SEQ ID NO: 31, ii) an scFv comprising the amino acid sequence of SEQ ID NO: 73, and iii) a hinge domain comprising the amino acid sequence of SEQ ID NO: 40; (b) a transmembrane domain comprising the amino acid sequence of SEQ ID NO: 33; (c) a co-stimulatory domain comprising the amino acid sequence of SEQ ID NO: 38; and (d) an endodomain comprising the amino acid sequence of SEQ ID NO: 36, the claims also broadly encompass generic CLRs comprising an ectodomain comprising a scFv comprising the amino acid sequence of SEQ ID NO: 73, a signal peptide comprising a human CD8α signal peptide and a hinge domain comprising a human CD8α hinge domain; a transmembrane domain comprising a human CD8α transmembrane domain; a co-stimulatory domain comprising a human 4-1BB costimulatory domain; and (d) an endodomain comprising a human CD3ζ endodomain. However, the claims and specification do not adequately describe each of the specific components of the CLR. For instance, the instant claims do not recite the specific signal peptide, hinge domain, or transmembrane domain of the human CD8α. Similarly, the claims do not recite the specific co-stimulatory domain or endodomain. Although the specification describes a few sequences corresponding to each of the signaling domains, hinge domains, and transmembrane domains, the scope of the claim is much broader than the sequences disclosed in the specification. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed CLRs without adequate descriptions of its component parts or overall makeup. The generically claimed ectodomain, transmembrane domain, costimulatory domain, and endodomain do not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the T cells expressing a CLR that specifically binds to c-KIT as recited in the claims, as written. Without knowing the complete structure of the claimed ectodomain, transmembrane domain, costimulatory domain, and endodomain, one would not be able to adequately describe the claimed CLR. The terms “ectodomain”, “transmembrane domain”, “costimulatory domain”, and “endodomain” do not provide specific structure(s) that correspond with each part of the CLR. Thus, the claims identify the CLR and its required domains solely by their function.
The claims also state that the T cells comprise an inducible caspase polypeptide, which comprises a ligand binding region, a linker, and a truncated caspase 9 polypeptide. However, the specification does not adequately describe the complete structure of the inducible caspase polypeptide. One of skill in the art would not be apprised of the complete structure of the polypeptide without a full description of its component parts.
Therefore, the specification does not provide adequate written description to identify the broad and variable genus of T cells comprising a CLR and an inducible caspase polypeptide because, inter alia, the specification does not disclose a correlation between the necessary structure of the T cell and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed T cell may generically describe its function, it does not describe the T cells itself. A definition by function does not suffice to define the genus because it is only an indication of what the T cell does, rather than what they are; therefore it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of T cells is highly variable (i.e. each T cell would necessarily have a unique CLR structure; see MPEP 2434), the functional characteristic of comprising (i) a CLR that binds to c-KIT, and (iii) an inducible caspase polypeptide and treating AML, is insufficient to describe the genus of T cells.
Additionally, the specification does not provide a representative number of species commensurate in scope of the genus. The specification discloses a CAR-T cell engineered via genetic modification using the non-viral PiggyBac transposon, targeting CD117 or CD133, and the safety switch iC9 for use in a method wherein HSC are cleared before transplantation of therapeutic HSCs. The specification demonstrates that depletion of HSC by said T cells targeting CD117 or CD133. Thus, the specification sets forth a correlation between a specific T cell engineered to express a specific CLR comprising a scFV against CD117 or CD133, and comprising an iC9, and the function of eliminating a target HSC. However, this correlation does not appear to be present in the breadth of the claims. As noted above, the claims encompass a vast genus of engineered T cells. With the exception of the T cells comprising their fully described components, the specification describes no other engineered T cells encompassed by the claims that have the function of treating AML. Given that the specification does not provide a correlation between the claimed engineered T cells, and the function of treating AML, and there is no indication that the species exemplified in the specification is predicative of other species within the genus, one of skill in the art would not know which T cells would have the required functions. Thus, the specification does not provide adequate guidance to carry out the claimed method commensurate in scope with the claims such that the recited T cells can be used to eliminate HSCs in a subject.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the cytokine per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Dotti et al. (Immunology Reviews, 2014: 257(1); 1-35) teach that the specificity of the generated CAR constructs was determined by epitope location, scFv affinity, hinge and transmembrane domains and number of signaling domains. Dotti et al. teach that there is an intricate interplay between scFVs, hinge, transmembrane domain and endodomain that determines CAR function and there is no single optimal configuration that is ‘one size fits all’. Therefore, CAR receptor optimization remains largely empirical, with testing required in a range of pre-clinical models (See page 4). Thus, Dotti et al. provides evidence that one of ordinary skill in the art would require specific guidance, rather than generic guidance as provided in the instant specification, when determining the components of the claimed CLR.
Taken together, the art provides evidence of the unpredictability when designing CLRs. Therefore, one of skill in the art would conclude that the claimed invention encompasses a genus of T cells comprising a CLR that may not have the function of treating AML. Applicant has provided little or no descriptive support beyond the mere presentation of generic or partially named structures to enable one of ordinary skill in the art to determine the actual structural composition of the claims genus of T cells. Although the prior art outlines art-recognized procedures for producing and screening for recombinant proteins this is not sufficient to impart possession of the genera of T cells to Applicant. Even if a few structurally identifiable composition components were described in the specification, they may not be sufficient, as the ordinary artisan would not necessarily immediately recognize how to put them together in such a way as to form a completely constructed chimeric antigen receptor such that one would be able to distinguish it from the chimeric antigen receptors of the prior art. Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of T cells as claimed.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed method which encompasses treating AML. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle& Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
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 220 is 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 220 contains the trademark/trade name piggyBac™. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe transposon and, accordingly, the identification/description is indefinite.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 210-225 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11744861. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are encompass treating AML in a subject comprising administering to the subject an effective amount of a composition comprising a plurality of T cells that express a chimeric ligand receptor (CLR) that specifically binds to c-KIT, wherein the CLR comprises:(a) an ectodomain comprising: i) a signal peptide comprising a human CD8α signal peptide; ii) a scFv comprising the amino acid sequence of SEQ ID NO: 73; and iii) a hinge domain comprising a human CD8α hinge domain; (b) a transmembrane domain comprising a human CD8α transmembrane domain; (c) a co-stimulatory domain comprising a human 4-1BB costimulatory domain; and (d) an endodomain comprising a human CD3ζ endodomain. Both sets of claims recite the same CLR, comprising the same sequences. Thus, the instant claims and the patent claims are of the same scope and not patentably distinct.
Claim Status
No claims are allowed.
Conclusion
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674