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 of the invention of Group I, and further election of various species of invention, all without traverse, in the remarks filed 6-3-26 are acknowledged.
Applicant has elected for initial examination on the merits the species of
TIM-binding domain which is an antibody that binds to SEQ ID NO: 97 (LPRQNH); or the species of TIM-binding domain which competes for binding to TIM-1 with an antibody comprising light and heavy chains 80-100% identical to the light and heavy chains of the "Ab2.70.2" antibody; or the species of TIM-binding domain which comprises light and heavy chains 80-100% identical to the light and heavy chains of the "Ab2.70.2" antibody;
The species of hinge based on a CD28 hinge;
The species of transmembrane domain based on the CD28 TMD;
The species of costimulatory domain based on a CD28 costimulatory domain; and
The species of intracellular signaling based on the CD3ζ signaling domain.
Upon further consideration the species of TIM-binding domain has been extended to further include “a single chain antibody” as recited in claim 51(a).
Claims 1 and 51-69 are pending.
Claims 1, 51-58 and 63 are under examination as they read on:
• The species of TIM-binding domain which is “a single chain antibody” or an antibody that binds to SEQ ID NO: 97 (LPRQNH); or the species of TIM-binding domain which competes for binding to TIM-1 with an antibody comprising light and heavy chains 80-100% identical to the light and heavy chains of the "Ab2.70.2" antibody; or the species of TIM-binding domain which comprises light and heavy chains 80-100% identical to the light and heavy chains of the "Ab2.70.2" antibody;
• The species of hinge based on a CD28 hinge;
• The species of transmembrane domain based on the CD28 TMD;
• The species of costimulatory domain based on a CD28 costimulatory domain; and
• The species of intracellular signaling based on the CD3ζ signaling domain.
Claims 59-62 and 64-69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim.
Election was made without traverse in the reply filed on 6-3-26.
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, 51-55, 58 and 63 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.
To satisfy the written description requirement, a patent 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. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116.
“[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). 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, binding to a certain epitope), claiming antibodies with specific properties, e.g., antibodies that as part of a CAR bind TIM-1, can result in a claim that does not meet written description even when the antigen(s) bound by the antibody is known, because antibodies with those properties have not been adequately described. See Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Along these same lines, as more recent Federal Circuit decision, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describes how when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself not just a description of the sequence to which the antibody binds. Amgen, 872 F.3d at 1378-79.
The importance of this court decision was recently expounded upon by Robert W. Bahr, Deputy Commissioner for Patent Examination Policy in a memorandum clarifying the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) as it relates to claims drawn to antibodies (see Memorandum of February 22, 2018, 2 pages, available at https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf).
Specifically, the so-called “newly characterized antigen” test, which had been based on an example in previously issued USPTO training materials and had been used in the past for determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody is now considered defunct.
The Memorandum explains that USPTO personnel should continue to follow the relevant sections of the MPEP pertaining to the written description requirement of 35 U.S.C. § 112(a) except insofar as the MPEP indicates that disclosure of a fully characterized antigen may provide written descriptive support of an antibody to that antigen.
In particular MPEP § 2163 instructs that 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…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 claimed genus…See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A "representative number of species" means that the species which are adequately described are representative of the entire 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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
Note well: 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 the instant case, the claims are drawn to biomolecules described only by their functional characteristic, such as antibodies that, as part of a CAR, bind TIM-1 (see, e.g., claim 1 and dependent claims thereof); or an antibody described by its ability to bind to the TIM-1 epitope “LPRQNH” SEQ ID NO: 97 (see, e.g., claim 51(c)); or an antibody having a Vh ≥ 80% identity to the amino acid sequence of the Vh of Ab 2.70.2 and having a Vl ≥ 80% identity to the amino acid sequence of the Vl of Ab 2.70.2 (see, e.g., claim 52(i)); or an antibody; or an antibody that competes for binding to TIM-1 with an antibody comprising a Vh ≥ 80% identity to the amino acid sequence of the Vh of Ab 2.70.2 and/or a Vl ≥ 80% identity to the amino acid sequence of the Vl of Ab 2.70.2 (see, e.g., claim 51(d)).
However, claiming antibodies only by their functional characteristic in the absence of a disclosed correlation between that function and the structure of the antibody sequence normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995).
In the instant case, the specification does not disclose representative members of the genus of antibodies encompassed by the instant claims. Rather, the instant specification discloses three anti-TIM-1 antibodies: 1.29, 2.70.2 and 2.59.2, that “were shown to bind to different epitopes on TIM-1” and points the reader to U.S. Patent No. 8,067,544 for more information.
Neither the instant specification nor U.S. Patent No. 8,067,544 disclose what structure(s) an antibody must have to specifically recognize and bind TIM-1; or to bind to the TIM-1 epitope “LPRQNH”; or which particular variants having a Vh ≥ 80% identity to the amino acid sequence of the Vh of Ab 2.70.2; or which particular variants having ≥ 80% identity to the amino acid sequence of the Vl of Ab 2.70.2; or what structure(s) an antibody must have to compete for binding to TIM-1 with an antibody comprising a Vh ≥ 80% identity to the amino acid sequence of the Vh of Ab 2.70.2 and/or a Vl ≥ 80% identity to the amino acid sequence of the Vl of Ab 2.70.2.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Applicant has not described the claimed invention sufficiently to show they had possession of the genus of antibodies that, as part of a CAR, bind TIM-1 (see, e.g., claim 1 and dependent claims thereof); or an antibody described by its ability to bind to the TIM-1 epitope “LPRQNH” SEQ ID NO: 97 (see, e.g., claim 51(c)); or an antibody having a Vh ≥ 80% identity to the amino acid sequence of the Vh of Ab 2.70.2 and having a Vl ≥ 80% identity to the amino acid sequence of the Vl of Ab 2.70.2 (see, e.g., claim 52(i)); or an antibody; or an antibody that competes for binding to TIM-1 with an antibody comprising a Vh ≥ 80% identity to the amino acid sequence of the Vh of Ab 2.70.2 and/or a Vl ≥ 80% identity to the amino acid sequence of the Vl of Ab 2.70.2 (see, e.g., claim 51(d)).
A priori, the number of antibodies encompassed by the claims is very unpredictable. It is possible a high frequency of antibodies can be generated that bind TIM-1, or that bind the TIM-1 epitope “LPRQNH,” or that have certain Vh and Vl domains ≥ 80% identity to the Vh and Vl domains of the Ab 2.70.2 antibody, or that will compete with an antibody having Vh and Vl domains ≥ 80% identity to the Vh and Vl domains of the Ab 2.70.2 antibody, but it is just a likely that such antibodies are exceptionally difficult to identify.
The specification fails to provide sufficient direction or guidance as to the particular structural elements necessary to put the skilled artisan in possession of the claimed genus of antibodies.
The skilled artisan knows the immune response to any given immunogen, and, in turn, the structure of an antibody produced during the immune response is a function of a number of unpredictable factors including, e.g., the precise structure of the immunizing antigen, the method of immunization, and the process of antibody variation, i.e., the immune response is very sensitive.
For example, Harlow et al. (Antibodies, A Laboratory Manual, Cold Spring Harbor laboratory, 1988, pages 37-47 and 55-59, cited herewith) teaches the process by which an antibody response occurs to an immunizing antigen and the method of immunization (see entire document). Many steps in this process are dependent on APC, T-cell and B-cell recognition and processing of the immunizing antigen in ways which are well known in the art to be highly unpredictable and heavily influenced by the particular immunizing antigen and the specific immunization method (see, e.g., the teachings of Mach 7,728,114, cited herewith, at Example 5 for but one example).
Again, as described above the number of antibodies having the functional features recited in the instant claims may be vast or they may be small; regardless what is certain is that the number of antibodies that would need to be screened to determine if one has obtained members of the claimed genera representative of their potential diversity is vast.
The principals laid out in Harlow are further illustrated in the teachings of Edwards et al. (J. Mol. Biol. (2003) 334, 103–118, cited herewith) which shows the immense combinatorial flexibility and capacity of the human antibody repertoire to generate binding sites to an individual protein antigen, the B-lymphocyte growth factor known as “BLyS” (see entire document). Edwards describes in detail how the breadth of antibody structures against a given immunogen can be influenced by the immunization and/or selection methods (see Discussion Section). Moreover, the teachings of Mach 7,728,114 at Example 1 provide an example of the diversity of immunization protocols.
Like Edwards, Lloyd et al. shows a repertoire of 1x1011 human antibody variable regions can generate large numbers of structurally unique, biologically active scFvs against a variety of polypeptide targets (see Lloyd et al., Protein Engineering, Design & Selection vol. 22 no. 3 pp. 159–168, 2009, e.g., at page 161-62 bridging paragraph and in Table 1, cited herewith).
As yet another example to illustrate the potential scope of the genus of antibodies encompassed by the instant claims, consider the teachings of Meyer et al. (British Journal of Haematology, 2018, 180, 808–820, Supp Figs S1-S4 and pages 1-5, cited herewith). Meyer describes the core binding region of the well-known anti-CD20 antibody rituximab corresponds to amino acid residues 170-ANPS-173, wherein N171 is the key residue for binding. By contrast, the OBZ and B1 anti-CD20 antibodies share an overlapping epitope with rituximab (170-ANPSEKNSP-178); however, in contrast to rituximab residues at positions 176–178 contribute the most to binding (see page 809, left col., 2nd full paragraph).
Meyer also described the production and characterization of a panel of new anti-CD20 antibodies which were shown to bind epitopes contained within or nearby the rituximab 170-ANPS-173 epitope but to bind to different residues than rituximab binds in this region (see page 811, “New CD20 mAbs with overlapping, but distinct epitopes,” see also page 815-16 bridging paragraph).
More particularly, Meyer teaches the newly created anti-CD20 mAbs m1 and m2 were found to bind within but also in the vicinity of the rituximab binding site (m1 and m2) and elsewhere (m2):
“detailed epitope mapping was performed for both mIgG2c-CD20 mAbs m1 and m2, by using PepScan technology. We identified the critical residues of m1 to be 168EPANPSEK175 by using linear (Figure S2A) and circular (Fig 2C, left) peptides with a positional amino acid scan covering the larger extracellular loop. Also for m2, a signal decrease below the WT binding signal occurred within the 168EPANPSEK175 sequence motif but the binding signal to the linear (Figure S2B) and circular (Fig 2C, right) peptide was rather low. This suggests that the epitope of both mAbs is located on the larger loop in the same region, however their binding characteristics are different. The data suggests that m1 binds a linear epitope, whereas m2 binds to a conformational epitope.”
(see ibid).
Moreover, while these antibodies bind within or nearby the rituximab 170-ANPS-173 epitope they do so with heavy and light chain CDRs non-homologous to those of rituximab.
Thus, even if multiple antibodies bind epitopes within the same small region of a given polypeptide it is not uncommon for said antibodies to bind to different amino acids even within said small region and for said antibodies to have structurally dissimilar CDRs.
When the above is taken together it is evident that the teachings of the instant specification fail to provide sufficient direction or guidance to put the skilled artisan in possession of the antibodies required to practice the claimed method. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Finally, note that post-effective-filing-date evidence can be relied upon to show that a patent failed to disclose a representative number of species of a claimed genus, see Amgen Inc. v. Sanofi, 872 F.3d 1367, 1375, 124 USPQ2d 1354, 1359 (Fed. Cir. 2017)(MPEP § 2124).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 51-55 are rejected under 35 U.S.C. 102(a)(l) and 35 U.S.C. 102(a)(2) as being anticipated by Loew et al. (WO2015142675, cited herewith).
Loew teaches an isolated chimeric antigen receptor (CAR), wherein the CAR comprises: (I) a single chain antibody antigen-binding domain, such as an scFv, that binds to T-cell immunoglobulin and mucin domain 1 (TIM-1), also known as "Hepatitis A virus cellular receptor" ("HAVCR") in the art (see instant specification at paragraph 8); (II) a transmembrane domain, such as a CD28 transmembrane domain; and (III) an intracellular signaling domain comprising a CD28 costimulatory domain and a CD3ζ primary signaling domain, wherein said antigen-binding domain of (I) is joined to said transmembrane domain of (II) by a "hinge." (see paragraphs 7, 9, 32, 34, 38, 39, 65, 331-333, 337, 345-348, 487-488).
Thus, the teachings of Loew anticipate the instant claims.
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.
Claim 63 is rejected under 35 U.S.C. 103 as being unpatentable over Loew et al. (WO2015142675) as applied to claims 1 and 51-55 above, and further in view of Cooper et al. (WO2014190273, cited herewith) as evidenced by Harlow et al. (“Using Antibodies, A Laboratory Manual,” Cold Spring Harbor Laboratory, 1988, pages 34-47 and 55-59, cited herewith).
The teaching of Loew are set forth above.
However, Loew does not explicitly teach the pharmaceutical composition of claim 63 comprising a pharmaceutically effective amount of the CAR of claim 1, and a pharmaceutically effective carrier or excipient.
Cooper teaches “…an antibody or a fragment thereof that binds to at least the CH2-CH3 hinge of
CAR protein (all-CAR)….” (see para 62). At para 130 Cooper teaches the production of an antibody that binds to the CH2-CH3 hinge of a CAR protein by administering NSO cells expressing a particular CH2-CH3 hinge comprising CAR to a BALB/c mouse, and goes on to show that such an antibody, when made to cross-link a CAR via expression of the antibody on the surface of K562 aAPC, is capable of inducing proliferation of a CAR-expressing T-cell (see paras 130-133).
Given the reference teachings it would have been obvious to one of ordinary skill in the art to make a pharmaceutical composition comprising a pharmaceutically effective amount of the HAVCR-binding CAR of Loew for the purpose of triggering an immune response in an appropriate recipient, such as mouse, thereby provoking the production of anti-CAR antibodies. The ordinarily skilled artisan would have been motivated to make such a CAR comprising pharmaceutical composition for use as an immunogen since it was well known to the skilled artisan that immunization with immunogens of interest in differing formats, e.g., in the context of a pharmaceutical composition versus expressed on the surface of a cell, provides greater opportunity for successfully producing the desired anti-CAR antibody since the interaction of the immunogen with the humoral immune system is influenced by a multitude of unpredictable factors as evidenced by Harlow, see especially pages 55-59.
No claims allowed. However, claims 56 and 57 are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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