DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendments and remarks filed 5/26/26 are acknowledged. Claims 60, 63, 69, 73, 74, 75, and 76 have been amended. Claims 1-59 have been canceled. Claims 80-82 have been added. Claims 60-82 are pending.
Claims 78-79 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1/27/26.
Claims 60-77 and 80-82 are pending and under examination as they read on the elected species.
New Rejection Necessitated by Applicant’s Amendment
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 60-72 and 77 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 an antibody conjugate represented by the structure of formula I: [CY-La-]m- Ab -[Lb-STING]n, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, regioisomer, or mixture of regioiosomers thereof, wherein Ab is an anti-Trop2 antibody or antigen-binding fragment thereof; and wherein Ab is an anti-TROP2 antibody or antigen-binding fragment thereof; and wherein the antibody or antigen-binding fragment thereof comprises three CDRs of a heavy chain selected from the group consisting of SEQ ID NOS: 12, 13, 15, and 16, and three CDRs of a light chain selected from the group consisting of SEQ ID NOS: 14 and 17, subscript n is an integer selected from one to ten; subscript m is an integer selected from one to ten; Lb-STING is a structure selected from…; [CY-La-]m is a structure selected from…; wherein
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is the point of attachment to the rest of the formula.
The specification discloses specific anti-Trop2 antibodies that bind to TROP2. Each antibody is described by the VH/VL sequences and specific CDR sequences.
Although the claims clearly set forth a correlation between the specific antibodies comprising discrete VH/VL and HCDR1-3 and LCDR1-3 combinations in the specification and the function of binding to TROP2, this correlation is not found within the breadth of the claims, which allows for substantial antibody structure variation. The claims state that the anti-TROP2 antibody comprises three CDRs of a heavy chain selected from the group consisting of SEQ ID NOs: 12, 13, 15, and 16, and three CDRs of a light chain selected from the group consisting of SEQ ID NOs: 14 and 17. Claim 1 allows for unlimited mixing and matching of the CDR sequences. However, the specification provides no guidance regarding which randomly chosen CDR sequences would have the claimed function of binding to TROP2. Absent empirical determination, one of skill in the art would not be able to determine which combination of heavy and light chain CDR sequences may be comprised within an antigen-binding site such that said antigen-binding site is capable of binding to TROP2. Given that the claims allow for mixing and matching of CDR sequences, there are hundreds, if not thousands, of possible antibodies encompassed by the claims. These antibodies have no correlation between their structure and function.
Thus, the claims encompass a vast genus of antibodies that have required function(s). However, the specification provides limited guidance on the structure required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of antibodies because, inter alia, the specification does not disclose a correlation between the necessary structure of the antibody and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. 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 antibody may generically describe the antibody’s function, it does not describe the antibody itself. A definition be function does not suffice to define the genus because it is only an indication of what the substance 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 substances is highly variable (i.e., each antibody would necessarily have a unique structure, See MPEP 2434), the generic description of the antibody is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
Furthermore, Applicants have not shown possession of a representative number of species of antibodies that bind to TROP2. As noted above, the claims broadly encompass antibodies with mixed and matched CDR sequences. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. While the specification clearly sets forth a correlation between the anti-TROP2 antibodies comprising discrete VH/VL and HCDR1-3/LCDR-1-3 combinations in the specification and the function of binding to TROP2, this correlation does not appear to be clearly present in the breadth of the instant claims. 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.
MPEP §2163 states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance (as in the instant case), the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. The courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g., see In re Gostelli, 872, F. 2d at 1012, 10 USPQ2d at 1618).
Further, the disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the genu[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when… the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claimed, claimed only be a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous antibodies had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of antibodies claimed only by a partial structure and functional characteristic(s).
Abbvie v. Centocor (Fed. Cir. 2014) is elevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. The instant claims are similar to the Abbvie antibodies because only a few closely related antibodies have been described for a broad genus of antibodies described only by function and/or a partial structure.
Further, in Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, 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 at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). 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). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362). In the instant application, neither the art nor the specification provides a structure-function correlation or a representative number of species to meet the written description requirements. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies, 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.
Finally, 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.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. Paul (Fundamental Immunology, 3rd Edition, Raven Press, New York, Chapter 8, pages 292-295, 1993) teaches that the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (See pages 293-295). While some publications acknowledge that CDR3 is important for antigen binding, the conformations of other CDRs as well as the framework are equally important in antigen binding. For example, MacCallum et al. (Journal of Molecular Biology, 262:732-745, 1996) analyzed antigen-contacting residues and combining site shape of various antibodies and state that although CDR3 of the heavy chain and light chain dominate, a number of residues outside of the standard CDR definitions make antigen contacts (See page 733). MacCallum et al. teach that antigens tend to bind to the antibody residues located at the center of the combining site where the six CDRs meet (See abstract and page 742) and less central CDR residues are only contacted by large antigens (See page 733 and 735). MacCallum et al. further teach that non-contacting residues are important in defining "canonical" backbone conformations.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is further underscored by Casset et al. (Biochemical and Biophysical Research Communications, 307:198-205, 2003), which discuss the importance of multiple CDRs in antigen contact. Casset et al. teach that all antibodies have six CDR residues, all of which are more or less involved in antigen recognition (See page 199). Casset et al. teach that peptide mimetics of antibody combining sites have previously only targeted CDR H3, since this CDR is typically at the center of most, if not all, antigen interactions; however, this strategy is flawed since other CDRs play an important role in the recognition of antigen (See page 199). Casset et al. construct a peptide mimetic of an anti-CD4 monoclonal antibody, containing antigen contact residues from five CDR regions, except L2 and additionally using a framework residue located just before the H3 and show that the peptide has high binding to CD4, thus signifying the contribution of multiple CDRs, and not a single CDR, in antigen recognition (See page 202 and Figure 4).
Vajdos et al. (Journal of Molecular Biology, 2002 Jul 5;320(2):415-28) additionally teaches that, “... 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.
Further, Sela-Culang et al. 2013 (The structural basis of antibody-antigen recognition; Frontiers in Immunology 4(302):1-13) teach the hypervariable loops within the variable domains of antibody polypeptides are widely assumed to be responsible for antigen recognition while the constant domains are believed to mediate effector activation, but that recent analysis indicates that their clear functional separation between the two regions is an over-simplification (see abstract). Sela-Culang et al. teach some residues within the CDRs may not participate in antigen binding and some residues outside the CDRs (e.g. in framework regions and in the constant domains) often contribute critically to the integration with the antigen (see abstract). Sela-Culang et al. teach understanding the role of each structural element is essential for successful engineering of binding polypeptides (e.g. page 2, left column). Sela-Culang et al. teach almost all of the residues predicted to be part of an epitope may be considered as correct predictors as they will bind to some antibodies but also are false predictors as they don’t bind to the others and accordingly that predicting that a residue is not in an epitope may be either a true negative or a false negative depending on the anybody considered (page 2, right column). Sela-Culang et al. teach each CDR has its own unique amino-acid composition different from the composition of the other CDRs and that each CDR has a unique set of contact preferences favoring certain amino acids over others (page 5-6, bridging). Sela-Culang et al. teach the combined action of all six CDRs is the evolutionary response of the immune system that enables the antibody polypeptide to recognize virtually any surface patch on the antigen (page 6). Thus, the state of the art recognized that it is highly unpredictable that an antibody comprising one or even all six CDRs, wherein the CDRs are not in their proper order or in the context of framework sequences which maintain their required conformation would have the requisite antigen binding function. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the antibody 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.
The state of the art is such that the location or site of conjugation on the drug and the antibody affect conjugate stability, and pharmacokinetics of antibody drug conjugates. For example, Strop et al (Chemistry and Biology 20: 161-167, 2013) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rat or nonhuman primates (See page 166- 168).
Although antibody drug conjugate (ADCs) hold promise for cancer therapy, cytotoxic drugs are generally conjugated to the antibodies via lysine side chains or by reducing interchain disulfide bonds present in the antibodies to provide activated cysteine sulfhydryl groups. This non-specific conjugation approach, however, has numerous drawbacks. Not only is it capable of affecting protein folding by disrupting cystine bonds, non-specific conjugation creates a heterogeneous mixture of antibodies having a diverse mix of antibody-to-drug ratios (ADR) and also having a complex mixture of antibodies conjugated at a variety of positions. So, even if it was somehow possible to purify sufficient antibodies having a desired antibody:drug ratio, the fraction would still comprise a complex mix of antibodies conjugated at various positions. Each species could potentially have distinct therapeutic properties, and batch-to-batch consistency would be difficult to control, all of which present significant hurdles to success of using ADC for cancer therapy.
Therefore, it appears that the instant specification docs not adequately disclose the breadth of the antibody-drug conjugate encompassed by the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all the said antibody-drug conjugates at the time the instant specification was filed, and hence, not in possession of method of using said antibody drug conjugate at the time the instant specification was filed.
Accordingly, one of skill in the art would conclude that the claimed invention encompasses a plurality of antibodies defined solely in terms of their function and/or comprising a partial structure that may not have the biological functions recited in the claims. Based on the teachings of the instant specification and the prior art, one of skill in the art would not conclude that Applicant was in possession of the claimed genus of antibodies.
While “examples explicitly covering the full scope of the claim language” typically will not be required, a sufficient number of representative species must be included to “demonstrate that the patentee possessed the full scope of the [claimed] invention.” Lizardtech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724, 1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Status
Claims 73-76 and 80-82 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.
No claims are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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