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 .
Applicant’s election without traverse of group I, claims 72-88 in the reply filed on 6/8/26 is acknowledged.
Claim 89 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/8/26.
Claims 72-88 are under examination.
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 72-73 and 75-88 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
The instant claims are drawn to a method of treating a lymphoma or myeloma, comprising administering to a subject in need thereof a therapeutically effective dose of cells expressing a chimeric antigen receptor (CAR), wherein the CAR comprises (i) a D domain that binds to BCMA (B cell maturation antigen) and comprises amino acid residues 21 to 93 of SEQ ID NO: 1166 or a sequence having at least 90% sequence to amino acid residues 21 to 93 of SEQ ID NO: 1166, and (ii) amino acid residues 94 to 327 of SEQ ID NO: 1166.
The specification teaches that NSG mice were engrafted with MM.1S tumor cells and 14 days later, received T cells transduced with a CAR expressing a BCMA specific D domain (bc-CAR, SEQ ID NO: 1166) (“ddBCMA-CAR”) or T cells transduced with a p26-binding CAR (Af101, SEQ ID NO: 1164) (“ARC-T cells”). The specification teaches that administration of T cells transduced with the p26-binding CAR in combination with the BCMA specific Adapter eliminated MM.1S tumor cells in vivo comparably to the tumor cell elimination by the T cells transduced with a CAR comprising a BCMA specific D domain.
Although the claims are inclusive of a CAR comprising (i) amino acid residues 21-93 of SEQ ID NO: 1166 and amino acid residues 94-327 of SEQ ID NO: 1166, (ii) amino acid residues 21-327 of SEQ ID NO: 1166, and the (iii) the full-length sequence set forth in SEQ ID NO: 1166, the claims also broadly encompass a vast genus of CARs comprising a sequence having at least 90% sequence identity to amino acids 21-93 of SEQ ID NO: 1166 and amino acid residues 94-327 of SEQ ID NO: 1166. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance of 10%, for example, in a sequence having 90% sequence identity to residues 21-93 of SEQ ID NO: 1166 that is 73 amino acids in length translates into 7 amino acids that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 72 residue amino acid sequence. To give an idea of the breadth of the claims, there are an almost unfathomable number of ways which 1 to 7 amino acids (i.e., the sum of results for 1 change, 2 changes, 3 changes…7 changes) can be selected from the 73 residues because, without any other limitation in the independent claims, each particular residue can be substituted with any of the other 19 naturally occurring amino acids and still meet the limitation. For example, for just 1 change, there would be 73 unique sequences, but because the change at each residue can be substituted with any one of the other 19 naturally occurring amino acids, then the actual number of unique sequences encompassed is 1,387 (i.e. a sequence having a substitution at, for example residue 33 with cysteine, would be structurally distinct from a sequence having a substitution at residue 33 with tryptophan; and 73*19=1,387). Yet, the claims allow for up to 8 unrestricted changes, anywhere along the length of amino acids 21-93 of SEQ ID NO: 1166, so with the order of selection not important and repetition not allowed, the equation is X = 19* [n!/(r!(n -r)!)], which for 7 changes, results in a number having more than 40 zeros (i.e., a trillion only has 12 zeros). As a result, there are potentially trillions of variant permutations that could be made and still maintain a variance of 0-7 amino acid substitutions. It should be noted that this example is for only one portion of the CAR polypeptide, and consideration of the other portions of the CAR polypeptide would exponentially increase the breadth of the claims. Therefore, these structures (i.e., D domain sequence variants) are claimed only by their functional characteristics and the specification fails to provide a sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domain within the sequence).
Therefore, the specification does not provide adequate written description to identify the broad and variable genus of the claims because, inter alia, the specification does not disclose a correlation between the necessary structure of the variant polypeptides (and the claimed function to be maintained; 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 the members of the genus, because, while the description of an ability of the claimed protein may generically describe the protein’s function, it does not describe the protein itself. A definition by function does not suffice to define the genu because it is only an indication of what the protein does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of CAR polypeptides is highly variable (i.e., each CAR polypeptide would necessarily have a unique structure, See MPEP 2434), the generic description of the variant sequence is insufficient to describe the genus. Further, given the highly diverse nature of proteins, even one of skill in the art cannot envision the structure of the modified polypeptide only by knowing its functional characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of CAR comprising a variant sequences of SEQ ID NO: 1166 claimed only by a functional characteristic and/or partial structure.
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between a CAR that binds to BCMA and comprises (i) amino acid residues 21-93 of SEQ ID NO: 1166 and amino acid residues 94-327 of SEQ ID NO: 1166, (ii) amino acid residues 21-327 of SEQ ID NO: 1166, and the (iii) the full-length sequence set forth in SEQ ID NO: 1166, the claims also broadly encompass a vast genus of CARs comprising a sequence having at least 90% sequence identity to amino acids 21-93 of SEQ ID NO: 1166 and amino acid residues 94-327 of SEQ ID NO: 1166 this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the full length sequence set forth in SEQ ID NO: 1166, and broadly encompass CARs comprising variant polypeptides. Thus, the genus of variant MLKL polypeptides has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be representative of the breadth of the genus. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of variant MLKL polypeptides claimed only by a partial structure and functional characteristic(s).
Vas-Cath Inc. v. Mahurkar, 19 US5PQ2d 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.)
With the exception of a CAR comprising (i) amino acid residues 21-93 of SEQ ID NO: 1166 and amino acid residues 94-327 of SEQ ID NO: 1166, (ii) amino acid residues 21-327 of SEQ ID NO: 1166, and the (iii) the full-length sequence set forth in SEQ ID NO: 1166, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
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 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 proteins 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.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). 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 Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). 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).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
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 (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 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.
Claim(s) 72-73 and 75-88 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hilbert et al. (WO 2019/099440 A1, published May 23, 2019).
The instant claims are drawn to a method of treating a lymphoma or myeloma, comprising administering to a subject in need thereof a therapeutically effective dose of cells expressing a chimeric antigen receptor (CAR), wherein the CAR comprises (i) a D domain that binds to BCMA (B cell maturation antigen) and comprises amino acid residues 21 to 93 of SEQ ID NO: 1166 or a sequence having at least 90% sequence to amino acid residues 21 to 93 of SEQ ID NO: 1166, and (ii) amino acid residues 94 to 327 of SEQ ID NO: 1166.
Hilbert et al. teach a method of treating myeloma comprising administering cell expressing a chimeric antigen receptor (CAR) comprising a (i) D domain that binds to a first antigenic determinant (AD), (ii) a transmembrane domain, and (iii) an intracellular domain; and (b) an Adapter which comprises (i) said first AD and (ii) an ADBD that binds to a second AD on a target cell (See paragraphs 011 and claim 1). Hilbert et al. teach that the antigenic domain is BCMA (See claim 1 and paragraphs 0085, 0251, and 0697). It should be noted that the CAR set forth in SEQ ID NO: 1091 shares 96.5% sequence identity with amino acids 21-93 and shares 96.5% sequence identity with amino acid residues 94-327 of SEQ ID NO: 1166. Hilbert et al. teach that the cell expressing the CAR is an immune effector cell (See paragraph 0063 and 85). Hilbert et al. teach the immune effector cell is a T cell or an NK cell (See paragraph 0085). Hilbert et al. teach that the myeloma is multiple myeloma (See paragraph 0085). Hilbert et al. teach that the administration of the CAR cells is intravenous (See paragraph 05551).
Query Match 96.5%; Score 363; Length 343;
Best Local Similarity 95.9%;
Matches 70; Conservative 1; Mismatches 2; Indels 0; Gaps 0;
Qy 1 MGSWSEFWARLGAIRERLDALGGSEAELAAFEKEIAAFESELQAYKGKGNPEVEKLRYTA 60
|||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||
Db 37 MGSWSEFWVRLGAIRERLDALGGSEAELAAFEKEIAAFESELQAYKGKGNPEVEKLRYTA 96
Qy 61 GTIKRFLQAYRHN 73
||:|||||||||
Db 97 ATIRRFLQAYRHN 109
Query Match 99.5%; Score 1256; Length 343;
Best Local Similarity 99.6%;
Matches 233; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 GGGGDGGGGSGTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW 60
|||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 110 GGGGSGGGGSGTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW 169
Qy 61 APLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 170 APLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGC 229
Qy 121 ELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 230 ELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 289
Qy 181 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 234
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 290 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 343
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108
836
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Greyscale
Hilbert et al. do not teach a sequence comprises amino acids 94-327 of SEQ ID NO: 1166.
However. Hilbert et al. teach that linkers are peptide or other chemical linkages located between two or more otherwise independent functional domains of the Adapter or CAR (See paeragraph 0229). Hilbert et al. teach that the linkers in the CAR are made of one or more amino acids selected from glycine, alanine, proline, asparagine, aspartic acid, threonine, glutamine, and lysine (See paragraph 0231). Hilbert et al. teach that one or more linkers in the Adapter or CAR comprises the sequence of Gly-Gly-Gly-Gly-Asp-Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 40) (See paragraph 0231). Hilbert et al. teach that linkers can be of any size or composition so long as they are able to operably link a functional domain of the Adapter or CAR in a manner that enables the functional domain to function (e.g., the ability of an antigenic determinant binding domain to bind a target of interest) (See paragraph 0234).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the BCMA CAR set forth in SEQ ID NO: 1091 with the GGGGDGGGGS (SEQ ID NO: 40) linker between the BCMA D domain and the CD8H domain, as suggested by Hilbert et al., by selecting from a finite number of identified, predictable alternatives; namely, by choosing the GGGGDGGGGS (SEQ ID NO: 40) linker from among the specific linkers suggested by Hilbert et al. for linking the functional domains of the BCMA CAR. Although Hilbert et al. do not contain an actual reduction to practice of an BCMA CAR comprising the GGGGDGGGGS (SEQ ID NO: 40) linker, the reference teaches a BCMA CAR, and names the GGGGDGGGGS (SEQ ID NO: 40) linker as an example of a suitable linker for linking the functional domains of the CAR. Further, Hilbert et al. teach that any linker can be used, so long as they can link the functional domains of the CAR. Accordingly, one of ordinary skill in the art found it obvious to combine the prior art elements as claimed in a predictable manner to arrive at a CAR polypeptoide comprising a D domain that binds to BCMA and comprises a sequence having at least 90% sequence identity to amino acid residues 21-93 of SEQ ID NO: 1166 and amino acids 94-327 of SEQ ID NO: 1166, as claimed.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". The combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Regarding the dose of cells expressing the CAR, it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat myeloma or lymphoma with the CAR expressing cells at the doses of the instant claims because one of skill in the art would have been motivated to optimize dosing to maximize efficacy and minimize side effects. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine the optimum time frame for dosing of a known agent to treat a disease. The determination of a dosing schedule for any given drug is a matter of routine experimentation using well- established methods in the field, and can be reasonably expected to produce predictable results. Additionally, Hilbert et al. teach that the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art. Further, optimizing dosing schedules to achieve a desired clinical result is obvious because dosage and dosing frequency are art recognized result effective parameters in the pharmaceutical/medical arts.
Regarding the overlapping doses of the instant claims and the Brown reference, according to MPEP 2144.05, In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
Claim Status
Claim 74 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA CARTER whose telephone number is (571)272-2932. The examiner can normally be reached 8:00-5:00 pm.
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, Vanessa L. Ford can be reached at (571)272-0857. 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.
/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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