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 .
Claims 1-10 are pending and under examination.
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 1-10 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 a method of treating an autoimmune disease, such as multiple sclerosis, in a subject by administering to the subject a therapeutically effective amount of the itolizumab antibody, or by administering to the subject a therapeutically effective amount of the UMCD6 anti-CD6 antibody, does not reasonably provide enablement for treating the vast genus of any T-cell mediated disease or disorder in a subject, including treating T-cell mediated multiple sclerosis in a subject, by administering a therapeutically effective amount of any anti-CD6 antibody, including the anti-CD6 antibodies of the instant specification which comprising SEQ ID NOs: 1-6, or for making and use any variants of said anti-CD6 antibodies comprising SEQ ID NOs: 1-6 according to the claimed methods, wherein said variants “including only conservative sequence modifications.”
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The instant specification describes the production of transgenic mice that were made to express human CD6 and in which the murine CD6 gene has been knocked (“CD6 humanized mice”), and further teaches that experimental autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis, was induced in said CD6 humanized mice, and that treatment of said CD6 humanized mice with the mouse anti-human CD6 mAb known as “UMCD6” effectively treated CD6 in said CD6 humanized mice (see, e.g., Example 1, which begins at page 19, para 71).
Working Example 2 (which begins at page 28, para 100) describes “work directed to humanize an anti-CD6 mouse monoclonal antibody without sacrificing the binding affinity. The humanization was carried out using two approaches: one is phage display library-based 'framework assembly' method; the other is structure-based CDR (complementarily determining region) grafting with framework backmutations.”
With respect to Working Example 1 in particular, at para 84, the specification describes how CD4+ T cells isolated from naïve CD6 KO mice and cultured under Th1 or Th17 polarizing conditions produce lesser amounts of intracellular IFNγ and IL-17 than do control CD4+ T cells isolated from naïve WT mice, pointing to Fig. 3.
In paras 85-87 following this para, the specification describes various additional features that distinguish WT and CD6 KO T-cells, but the specification does not teach how the phenotype of CD6 KO T-cells relates to, e.g., the effect of anti-CD6 antibodies such as the itolizumab or UMCD6 antibodies on any one of the vast genus of “T-cell mediated diseases or disorders” encompassed in the breadth of the claimed methods of treatment, nor what effect the particular antibodies of claims 7-10 would have on any one of the vast genus of “T-cell mediated diseases or disorders” encompassed in the breadth of the claimed methods of treatment.
At para 88-90 the specification teaches the production of transgenic mice wherein murine CD6 has been knocked-out and further a cDNA encoding human CD6 has been inserted into “…a human CD2 promoter/locus control region to reproduce the relative restriction of human CD6 to T-cells. de Boer et al., Eur J Immunol 33: 314-325 (2013). After verifying the expression of human CD6 protein on lymphocytes in the resultant Tg mice….” (so called “hCD6 Tg”). Said hCD6 Tg mice were shown to be useful in the EAE model, and hCD6 Tg mice immunized with an EAE-inducing antigen were shown to be successfully treated by administration of the mouse anti-human CD6 antibody UMCD6.
Paras 91-92 of the specification teach:
“CD4+, CD8+ and CD6+ T cell populations did not significantly change between the treated and control groups (Fig.8), suggesting that UMCD6 mAb attenuated EAE disease severity in the CD6 humanized mice neither by T cell depletion nor by modulating CD6 on T cells,” and
“a mouse anti-human CD6 mAb (UMCD6) was shown to be highly effective in treating EAE without depleting T cells.”
According to para 97, “ltolizumab binds to domain 1 of CD6 (Alonso, R, et al., Hybridoma (Larchmt) 27(4): 291-301 (2008)) and it does not block the interaction between CD6 and its currently known ligand, CD166, which binds to domain 3 of CD6….,” and similar to the itolizumab antibody, the UMCD6 antibody “…also binds to domain 1 of CD6 and does not block CD6-CD166 interaction.”
Para 99 concludes, “…the inventor demonstrated that CD6 is required for the development of EAE. CD6 is a negative regulator of T cell activation, but a positive regulator of T cell proliferation and survival. Therefore, lack of CD6 leads to reduced T cell responses in EAE. In addition, CD6 on T cells is also required for T cell infiltration through the BBB into the CNS…. the inventor showed that human CD6 functions in mice, and identified UMCD6, a mouse anti-human CD6 mAb, as a potent inhibitor of EAE. These results encourage exploration of the potential of a humanized variant of an anti-CD6 antibody such as UMCD6 to become a new therapeutic for treating MS and possibly other diseases.”
However, the instant specification does not provide sufficient direction or guidance for the skilled artisan to use the particular antibodies recited in claims 7-10 to treat the vast genus of any T-cell mediated disease or disorder, including treating T-cell mediated multiple sclerosis.
For example, the instant specification does not disclose anything about the effect(s) that the Fab2 antibody, comprising the variable domains of SEQ ID NOs: 1 and 2, the Fab4 antibody, comprising the variable domains of SEQ ID NOs: 3 and 4, or the Fab6 antibody comprising the variable domains of SEQ ID NOs: 5 and 6, have on CD6+ T cells.
For example, in contemplating the treatment of the vast genus of any T-cell mediated disease or disorder, including treating T-cell mediated multiple sclerosis by administering the particular anti-CD6 antibodies of the instant claims the ordinarily skilled artisan would want to know
(i) do the Fab2, 4 and 6 antibodies down-modulate cell surface CD6, and/or depleting CD6 expressing cells, and/or neither down-modulate nor deplete CD6 expressing cells?;
(ii) are the Fab2, 4 and 6 antibodies capable of treating the EAE mouse model of Example 1?;
(iii) do the Fab2, 4 and 6 antibodies change the ability of CD4 T-cells cultured under Th1 or Th17 polarizing conditions produce intracellular IFNγ and IL-17?; and/or
(iv) do the Fab2, 4 and 6 antibodies bind to domain 1 of CD6 while not blocking the interaction between CD6 and CD166?
In the absence of such disclosure the skilled artisan would have little certainty about their ability to treat the vast genus of any T-cell mediated disease or disorder, including treating T-cell mediated multiple sclerosis, by administering any one of the Fab2, 4 and 6 antibodies to a subject having one of such diseases.
Indeed, at the time of applicant’s earliest filed application there was significant uncertainty in the prior art as to how even well a characterized anti-CD6 antibody, such as the itolizumab antibody, was capable of exerting its therapeutic effects when, e.g., “the mode of action of the
therapeutic CD6 mAbs is far from being understood, reflecting the uncertainties and controversy surrounding the mechanistic and biological functions of CD6… opposing the contribution of CD6 adhesiveness in the establishment and stabilization of immunological
synapses, the actual triggering of CD6 might induce anti-proliferative signals to the T lymphocyte…. In this review we discuss the multiple aspects that determine
the nature of the signals transmitted via CD6 and the context that may define a dual role for this important T cell surface molecule.” (see Santos et al., Current Drug Targets, July of 2016, 17, 630-639, cited herewith, at Abstract with emphasis added).
At page 635, left col., - page 637, left col, Santos describes how uncertainty surrounding the effects of anti-CD6 mAbs on CD6+ T cells, as well as the dual, and potentially opposing role of CD6 itself in T-cell function, makes predicting if any given anti-CD6 mAb with have no effect / a therapeutic effect / a pathogenic effect on the vast genus of any T-cell mediated disease a highly unpredictable endeavor (emphasis added):
“However, having all facts considered, even if immunotherapy with CD6 mAbs can be pondered as a treatment for this and other inflammatory diseases we are still at a stage where it is not easily predictable whether a given effect observed in vitro will have a corresponding outcome in vivo.”
“A fine line separates activation-induced proliferation from activation-induced cell death, and the development of immunotherapeutic protocols could benefit profusely from the clarification of the action of CD6 mAbs binding to target cells, in the proper cellular context and with a much deeper characterization of the molecular mechanisms induced.”
“Initially, the rationale was to use CD6 mAbs to deplete T cells, but the more recent trials employ non-depleting mAbs. Itolizumab [83], a humanized form of the CD6 mAb IOR-T1 [6], has been used to treat with success rheumatoid arthritis and chronic plaque psoriasis [84, 85]. It is a non-T cell depleting mAb, but also does not block the CD6-CD166 ligation [42], so its mode of action and how it interferes with CD6 signaling remains unknown. Past studies using cellular models have described that different CD6 mAbs may induce equivalent or divergent effects, some enhancing while others inhibiting T cell proliferation, and even having anti-apoptotic effects, depending on the presence or nature of the accessory cells, the class of the immunoglobulin, the CD6 epitopes targeted, and also on the individuality of each agonistic monoclonal antibody [6, 42, 86-93].”
“A thorough analysis of the molecular mechanisms involved in CD6-mediated pathways is therefore needed to elucidate the function of this important receptor of T lymphocytes and to devise precise strategies that, by perturbing key steps of damaged signaling pathways or restoring the function of deregulated cells, can offer renewed prospects of treating human disease.”
Additional uncertainty as to the function of CD6 in the context of the vast genus of any T-cell mediated disease or disorder is described by the instant specification at para 98 which points to the teachings of Orta-Mascaró et al., J. Exp. Med. 2016 Vol. 213 No. 8 1387–1397, cited herewith. As stated in the abstract of Orta-Mascaró, “The suppressive activity of CD6−/− Treg cells was diminished, and CD6−/− mice presented an exacerbated autoimmune response to collagen. Collectively, these data indicate that CD6 modulates the threshold for thymocyte selection and the generation and/or function of several peripheral T cell subpopulations, including Treg cells.”
Turning to the “ or variants thereof…” language of claims 7-10, as preliminary matter note that the phrase “variants thereof” given its broadest reasonable interpretation consist with the teachings of the instant specification (see para 0044) and the plain meaning this phase would have to the skilled artisan is interpreted to encompass any number of amino acid substitutions, insertion or deletions to the parent sequence, i.e., the Fab2, Fab4 or Fab 6 sequences, be they radical or conservative.
Thus, the phrase “…or variants thereof including only conservative sequence modifications” is interpreted to merely confirm for the reader that within the breadth of “variants/varients thereof” is included one embodiment with “only conservative sequence modifications.”
The skilled artisan would not understand the latter half of this phrase – “including only conservative sequence modifications” to limit the claim in any way so as to limit variants/varients thereof to only variants/varients which are conservative sequence modifications.
That said, the teachings of the instant specification and the knowledge in the art are insufficient to enable the skilled artisan to make and use the breadth of antibody variants encompassed by the instant claims.
The instant specification teaches the humanization of a parent anti-CD6 antibody wherein the CDRs of said antibody are grafted into homologous human framework regions and certain amino acids of the parental antibody are added back to the homologous human framework regions (“back mutations”) see Example 2 and Table 2.
Each of the humanized fab2, fab4 and fab6 antibodies have the same CDR sequences with various substitutions in their framework regions (see attached alignment, cited herewith). Moreover, each of these antibodies share the same light chain, SEQ ID NO: 2.
It was known in the art that antibody-antigen affinity and specificity was a function of not only direct CDR to antigen interactions, but also the interactions of the CDRs with framework residues in the same chain, e.g., Vh CDR binding to Vh framework residues, and in the opposing chain, e.g., Vh CDR binding to Vl framework residues. In addition, the CDR residues of each chain were known to interact with the CDRs of the opposite chain. It is for this reason that antibody humanization protocols, e.g., humanization of a murine antibody, provided extensive guidelines as to the retention of certain murine residues in the context of the human framework so as to preserve this web of interactions, the loss of any one of these interactions having the potential to ablate antibody-antigen binding (see, e.g., Eduardo Padlan, Mol Immunol. 1994 Feb;31(3):169-217, in particular column bridging paragraph on page 177; page bridging paragraph pages 178-179 through page 180; pages 201, 204 and Tables 8, 22 and 23 and Adair et al., United States Patent No. 5,859,205, in particular columns 1-6, 9-11 and 27-28, all cited herewith).
It is further accepted in the art that, in general, each of the CDRs in the antibody Vh and VL domains, and potentially any one or more of the amino acid residues contained within a given CDR are expected to contribute to antigen binding. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28, cited herewith) taught “[t]he specificity and affinity of an antibody for its cognate antigen is determined by the sequence and structure of the variable fragment (Fv): a heterodimer consisting of the N-terminal domains of the heavy and light chains. Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.” (see, page 416, column bridging paragraph, emphasis added).
Vajdos goes on to teach that "[b]y analyzing panels of point mutants, a detailed map of the
binding energetics can be obtained, but the process can be very laborious because individual
mutant proteins must be made and analyzed separately. In particular, a comprehensive analysis
of an antigen binding site would ideally encompass all CDR residues, and this would require the analysis of dozens or even hundreds of point mutants." (see page 416, right column, first
paragraph). Vajdos solution to this dilemma was to make use of a shotgun scanning mutagenesis which "uses phage displayed libraries of protein mutants constructed using degenerate codons with restricted diversity." While this method of making libraries of mutants representative of the potential antigen binding CDR residues was an improvement over previous strategies as taught by Vajdos, it nonetheless required extensive experimentation to comprehensively scan the potential CDR sequence space (see page 416, right column, 2nd paragraph and pages 425-427, Materials and Methods.)
Furthermore, even after performing this comprehensive scanning mutagenesis of all CDR
residues from the particular anti-ErB2 antibody under study, Vajdos would still not have been
able to say which CDR residues were actually involved in antigen binding, and which were
involved in stabilizing the secondary and tertiary structure of the CDRs within the context of the heavy and light chains as a whole, without the structure of the unbound antigen-binding site of the antibody to aid in their analysis (see, in particular, Discussion, pages 422-425).
Rather, Vajdos needed to perform not only a comprehensive shotgun scanning mutagenesis of all CDR residues of the antibody under study, but also needed a structure of the unbound antigen binding site in hand to gain a sufficient understanding of the contribution of each CDR to antigen-binding to adequately predict which CDR residues can be changed, and to what extent, or in what context of additional compensatory mutations in other regions of the antibody. Moreover, given an amino acid substitution that ablated binding, without the crystal structure in hand, still further experimentation would have been required to determine the flexibility in this particular residue, i.e., it's general tolerance or intolerance to change.
As yet another example to illustrate the unpredictable effects of changes to antibody CDR residues, especially CDR3 consider the teachings of Bedouelle et al. (FEBS J. 2006 Jan;273(1):34-46, cited herewith). While Bedouelle did not comprehensively scan all the CDR residues of their antibody using a combination of alanine and homologous substitutions as shown in Vajdos, Bedouelle did examine the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a >100 fold drop in binding affinity (see Table 1). As described by Bedouelle, some of these loss of function mutations were hypothesized to have a direct effect on antigen binding while others were hypothesized to indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section). Thus, the teachings of Bedouelle provide further illustration of the unpredictability of making mutations within the CDR region of an antibody.
Likewise, as to making antibodies having multiple mutations in each of the CDRs, an embodiment encompassed by the instant claims but not exemplified in the teachings of the instant specification, there is an additional level of unpredictability in the art. For example, even in those instances where one can show certain residues of a given CDR are generally tolerant of single amino acid changes, this does not necessarily mean a combination of single amino acid changes, even to the same residues shown to tolerate change when mutated in isolation, will be tolerated. See, e.g., Brown et al. (J Immunol. 1996 May 1;156(9):3285-91, cited herewith) which describes how the Vh CDR2 in a particular antibody was generally tolerant of single amino acid changes; however, the antibody lost binding upon the introduction of pairs of single amino changes in the same region (see Tables I and II and column bridging paragraph on page 3290).
Additionally, as emphasized by the teachings of Colman (Research in Immunology, 145:33-36, 1994, cited herewith) the type of CDR amino acid substitution, i.e., conservative vs. non-conservative, is not necessarily a good predictor of antigen binding: "[t]he above examples paint a confusing picture of the specificity of antibody-antigen interaction. In one structural context, a very conservative substitution may abolish binding; in another, a nonconservative substitution may have very little effect on the binding affinity.” (see pg. 35, top of left column). Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79: 1979-1983, March 1982, cited herewith) provides another example of how even a conservative change to a single amino acid residue in a CDR region of an antibody can ablate antigen binding (see, for example, Abstract).
When the above is considered together it is evident that undue trial and error experimentation would be required of the skilled artisan to make and use the enormous genus of antibodies encompassed by the instant claims in the absence of undue experimentation.
In sum, in view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, undue experimentation would be required to practice the claimed invention commensurate with the scope of the claims.
A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentech, Inc, v. Novo Nordisk, 42 USPQ 2d 1001,(CAFC 1997), the court held: “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable” and that “[t]ossing out the mere germ of an idea does not constitute enabling disclosure”. Further, “[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement”.
The instant specification provides insufficient teachings to guide the skilled artisan to make the genus of CD6-binding Fab2, Fab4 and Fab6 variants encompassed by the breadth of the claims. The claims encompass an invention of tremendous scope, and essentially calls for undue trial and error experimentation by the skilled artisan to begin discovering the breadth of the claimed invention that can be made and used according to the teachings of the instant specification, without assisting the skilled artisan in such an endeavor, which does not constitute adequate enablement.
In sum, in view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trial and error experimentation to practice the claimed invention.
Claims 1 and 5-10 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 pre-AIA 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., CD6-binding, 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 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). Bahr’s memo describes how the so-called “newly characterized antigen” test, which was 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 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 antibodies comprising an antigen-binding fragment selected from the group of antibodies consisting of Fab2, Fab4, and Fab6, or variants thereof including only conservative sequence modifications.
Thus, the breadth of the claimed genus is enormous encompassing antibodies having any number of amino acid substitutions, insertion or deletions to the parent sequence, i.e., the Fab2, Fab4 or Fab 6 sequences be they radical or conservative.
However, simply reciting a structure, e.g., antibodies having any number of amino acid substitutions, insertion or deletions to the parent sequence, i.e., the Fab2, Fab4 or Fab 6 sequences, be they radical or conservative, and its function, e.g., having binding specificity for CD6, provides insufficient 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).
Indeed, as shown in the attached alignment the heavy chain CDRs of SEQ ID NOs: 1, 3, 5, 11, 12 and 14-17 are completely conserved.
Conservation of the CDR residues is of particular importance because any number of Vh and VL CDR residues are expected, a priori, to contribute to antigen binding and yet the instant specification and the knowledge in the art do not establish which residues of the disclosed CD6-binding antibodies are structurally essential to antigen binding versus those that are tolerant to change, and to what degree, i.e., conservative or radical.
To illustrate this point, consider Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28) which teaches “[t]he specificity and affinity of an antibody for its cognate antigen is determined by the sequence and structure of the variable fragment (Fv): a heterodimer consisting of the N-terminal domains of the heavy and light chains. Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.” (see, page 416, column bridging paragraph, emphasis added).
Vajdos goes on to teach that "[b]y analyzing panels of point mutants, a detailed map of the
binding energetics can be obtained, but the process can be very laborious because individual
mutant proteins must be made and analyzed separately. In particular, a comprehensive analysis
of an antigen binding site would ideally encompass all CDR residues, and this would require the
analysis of dozens or even hundreds of point mutants." (see page 416, right column, first
paragraph). Vajdos solution to this dilemma was to make use of a shotgun scanning mutagenesis
which "uses phage displayed libraries of protein mutants constructed using degenerate codons
with restricted diversity." While this method of making libraries of mutants representative of the
potential antigen binding CDR residues was an improvement over previous strategies as taught
by Vajdos, it nonetheless required extensive experimentation to comprehensively scan the
potential CDR sequence space (see page 416, right column, 2nd paragraph and pages 425-427,
Materials and Methods.)
Furthermore, even after performing this comprehensive scanning mutagenesis of all CDR
residues from the particular anti-ErB2 antibody under study, Vajdos would still not have been
able to say which CDR residues were actually involved in antigen binding, and which were
involved in stabilizing the secondary and tertiary structure of the CDRs within the context of the
heavy and light chains as a whole, without the structure of the unbound antigen-binding site of
the antibody to aid in their analysis (see, in particular, Discussion, pages 422-425).
Rather, Vajdos needed to perform not only a comprehensive shotgun scanning mutagenesis of all
CDR residues of the antibody under study, but also needed a structure of the unbound antigen binding site in hand to gain a sufficient understanding of the contribution of each CDR to
antigen-binding to adequately predict which CDR residues can be changed, and to what extent,
or in what context of additional compensatory mutations in other regions of the antibody.
Moreover, given an amino acid substitution that ablated binding, without the crystal structure in
hand, still further experimentation would have been required to determine the flexibility in this
particular residue, i.e., it's general tolerance or intolerance to change.
As yet another example to illustrate the sensitivity of some antibodies to changes in their CDR residues, especially CDR3, consider the teachings of Bedouelle et al. (FEBS J. 2006 Jan;273(1):34-46). While Bedouelle did not comprehensively scan all the CDR residues of their antibody using a combination of alanine and homologous substitutions as shown in Vajdos, Bedouelle did examine the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a >100 fold drop in binding affinity (see Table 1). As described by Bedouelle, some of these loss of function mutations were hypothesized to have a direct effect on antigen binding while others were hypothesized to indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section). Thus, the teachings of Bedouelle provide further illustration of the unpredictability of making mutations within the CDR region of an antibody.
Notably, while the teachings of Vajdos and Bedouelle demonstrate the unpredictable effects of even single amino acid changes on antibody:antigen binding, there is an additional level of unpredictability in the art associated with making multiple changes in any given CDR(s).
In particular, even in those instances where one can show certain residues of a given CDR are generally tolerant of single amino acid changes, this does not necessarily mean a combination of single amino acid changes, even to the same residues shown to tolerate change when mutated in isolation, will be tolerated. As an example consider Brown et al. (J Immunol. 1996 May 1;156(9):3285-91) which describes how the Vh CDR2 in a particular antibody was generally tolerant of single amino acid changes; however, the antibody lost binding upon the introduction of pairs of single amino changes in the same region (see, in particular Tables I and II and column bridging paragraph on page 3290).
Additionally, as emphasized by the teachings of Colman (Research in Immunology, 145:33-36, 1994) the type of CDR amino acid substitution, i.e., conservative vs. non-conservative, is not necessarily a good predictor of antigen binding: "[t]he above examples paint a confusing picture of the specificity of antibody-antigen interaction. In one structural context, a very conservative substitution may abolish binding; in another, a nonconservative substitution may have very little effect on the binding affinity.” (see pg. 35, top of left column). Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79: 1979-1983, March 1982) provides another example of how even a conservative change to a single amino acid residue in a CDR region of an antibody can ablate antigen binding (see, for example, Abstract).
Given the above the skilled artisan cannot extrapolate from the disclosure of the instant specification to establish possession of the breadth of the breadth of CD3-binding variants encompassed by the instant claims. Note that while claim 1 does not explicitly state that the genus of antibodies binds CD3, the only utility for the claimed antibodies lies in the context of binding CD3.
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”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibody-like binding molecules because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of antibodies.
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) 1-6 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Melarkode et al. (20110002939, cited herewith).
Melarkode teaches a method of treating multiple sclerosis in a subject comprising administering a pharmaceutically effective dose of 0.1-25 mg/kg/week of the monoclonal, humanized isotype IgG1 anti-CD6 antibody “T1h” that binds to the D1 domain of CD6 present on the surface of, inter alia, activated T cells (see, e.g., paragraphs 1, 12, 76 and claims 19-21). Thus, Melarkode anticipates the claimed invention.
Claim(s) 1-6 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Nair et al. (WO2015011658, cited herewith).
Nair teaches a method of treating multiple sclerosis in a subject comprising administering a pharmaceutically effective dose of the monoclonal, humanized isotype IgG1 anti-CD6 antibody (see page 1-2 bridging paragraph – page 2, 1st full paragraph; page 3, last full paragraph; page 6-7 bridging paragraph; page 22, 1st and 2nd full paragraphs).
Claim(s) 1-6 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Nair et al. (10189899, cited herewith).
The US national stage filing of the ‘658 from above resulted in U.S. Patent No. 10189899 wherein claim 1 is drawn to “a method of treatment for multiple sclerosis in a subject, wherein the subject in need of such treatment exhibits an increased number of T helper 17 (Th17) cells when compared to a healthy subject, the method comprising: administering a humanized antibody that specifically binds to D1 of CD6 of the subject and causes a reduction of expression of IL-23R on one or more of monocytes, T helper cells and natural killer cells in a body fluid of the subject, wherein the humanized antibody is the only therapeutic antibody administered; and monitoring IL-23R expression on blood cells and/or dendritic cells of the subject,” and further wherein dependent claim 3 specifies “[t]he method of claim 1, wherein the humanized antibody is Itolizumab,” which is a monoclonal antibody.
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 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-13 of copending Application No. 18/252,928 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claims are allowed.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644