DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of group I, claims 126-143 and the species of an atni-TM4SF1 antibody comprising the sequences set forth in SEQ ID NOs: 90, 97, 94, 95, 96, 107, 109, 110 and 151; a ubiquitin E3 ligase binding group; target protein binding group; linker I; linker II in the reply filed on 8/13/25 is acknowledged.
Claims 144-145 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 8/13/25.
Claims 126-143 are under examination as they read on the elected species.
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 126-143 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The instant claims are drawn to a heterobifunctional compound that comprises:
(a) an anti-TM4SF 1 antibody or an antigen binding fragment thereof;
(b) a degrader molecule; and
(c) a first linker L1 between the anti-TM4SF1 antibody and the degrader molecule wherein the degrader molecule comprises:
(i) a single-ligand molecule that directly interacts with a target protein to induce degradation of the target protein; or
(ii) a chimeric degrader molecule comprising a specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER); or
(iii) a single-ligand molecule that interacts with an E3 ubiquitin ligases to modulate substrate selectivity of the E3 ubiquitin ligase; or
(iv) a ubiquitin E3 ligase binding group (E3LB) and a target protein binding group (PB).
The specification discloses anti-TMSF1 antibodies named AGX-A01, AGX-A03, AGX-A04, AGX-A05, AGX-A07, AGX-A08, AGX-A09, AGX-A11, AGX-A07 H2v1L5v2, AGX-A07 H2L5. The specification teaches various exemplary degraders (Brd4, BCL-XL, and Ak2) were conjugated to anti-TM4SF1 antibodies (See paragraph 00442). The specification teaches that example structures for Brd4 degraders are provided in figures 1 and 2 (See paragraph 00442). The specification teaches that one of the exemplary Brd4 degraders were conjugated to AGX-A07 anti-TM4SF1 antibody via a maleimide-valine-citrulline cleavable linker and the conjugate is shown in figure 4 (See paragraph 00442). The specification teaches other exemplary Brd4 degrader- anti-TM4SF1 antibody conjugates are shown in figures 6, 8, 12 (See figure 00443). The specification teaches that BCL-XL degraders were synthesized and are shown in figure 15 (See paragraph 00446-00447). The specification discloses an Akt degrader molecule in figure 16 (See paragraph 00449).
Although the instant claims are inclusive of the specific heterobifunctional compounds comprising full described anti-TM4SF1 antibodies and fully described degrader molecules, the claims are not limited to these compounds. The claims broadly encompass a vast genus of compounds comprising component parts that are not adequately described.
Regarding the anti-TM5SF1 antibody portion of the heterobifunctional compound, although the claims are inclusive of anti-TM5SF1 antibodies comprising a heavy chain comprising a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 8, 20, 32, 44, 56, 68, 80, 96, 118, 119, 120, or 121; a CDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 19, 31, 43, 55, 67, 79, 95, 116, or 117; and a CDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 18, 30, 42, 54, 66, 78, 94, or 115; and (b) a light chain comprising a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 26, 38, 50, 62, 74, 86, 110, 111, or 129; a CDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 25, 37, 49, 61, 73, 85, 109, or 128; and a CDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 24, 36, 48, 60, 72, 84, 107, 108, 124, 125, 126, or 127, the claims also include variants comprising CDR sequences that have at least 75% identity the aforementioned CDR sequences. The claims are also inclusive of the anti-TM5SF1 antibodies comprising a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 15, 27, 39, 51, 63, 75, 90, 92, 112, 114, 130, or 132, and a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 9, 21, 33, 45, 57, 69, 81, 97, 99, 101, 122, 131, or 133, as well are variants comprising heavy chain and light chain sequences that share 75% identity to the aforementioned sequences. Further compounding the breadth of the claims is that the antibody can further comprise a modified IgG Fc region, wherein the modified IgG Fc region comprises one or more substitutions at one or more positions selected from the group consisting of E233, L234, L235, G237, M252m S254, T250, T256. D265, N297, K322, P331, M428, and N434. Thus, the claims encompass an extremely large number of antibodies that have specific required functions. To give an idea of the breadth of the claims, CDR3 of the heavy chain must have at least 75% sequence identity to SEQ ID NO:8. SEQ ID NO:8 has 14 amino acids. To reach at least 75% identity, up to three amino acids can be varied at any position within the CDR. Mutating three sites out of fourteen residues results in 2,744 possible mutation site combinations. Leaving out the potential added complexity of substituting non-natural amino acids, substitutions at the sites can be selected from 19 other amino acids. Selecting three sites with 19 different amino acids gives over 6,859 possible combinations, and that is just for one set of substitution sites out of all the possible combinations. Therefore, there are thousands of possible antibodies when only considering the CDRs. Adding in further substitutions in the structural sequences attached to the CDRs will introduce further variation, producing millions of possible antibody sequence combinations. The specification discloses ten species within the instant claims scope and does not provide any guidance as to which amino acids can be varied while retaining the appropriate functions. 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. 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 variants thereof claimed only by a functional characteristic and/or a partial structure.
Regarding the degrader molecule of the heterobifunctional compound, while the claims are inclusive of heterobifunctional compounds comprising Brd4 and BCL-XL as the degrader component, the claims broadly encompass functionally defined degrader molecules of claims 126-128. The degrader has specific required functions; however, the specification does not provide any structure identifying information (e.g., the structure of the degrader molecule) such that one of skill in the art could readily envisage the degrader molecule of the heterobifunctional compound. Therefore, these structures (degrader molecules) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e. critical domains and structural motifs) that are essential and distinguish members of the genus from those excluded.
Thus, the genus of heterobifunctional compounds is extremely broad because the claims recite generic and incompletely described compounds. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed heterobifunctional compounds without adequate descriptions of its component parts or overall makeup. The generically claimed anti-TM4SF1 antibody and variants thereof and degrader molecule do not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the genus of heterobifunctional compounds recited in the claims. For instance, without knowing the structure of the claimed anti-TM4SF1 antibody and degrader molecule, one would not be able to adequately describe the claimed heterobifunctional compound. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of heterobifunctional compounds because, inter alia, the specification does not disclose a correlation between the necessary structure of the heterobifunctional compound and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function.
Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed compound may generically describe the proteins’ function, it does not describe the heterobifunctional compound itself. A definition by function does not suffice to define the genus because it is only an indication of what the heterobifunctional compound does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of heterobifunctional compounds is highly variable (i.e., each heterobifunctional compound would necessarily have a unique structure; see MPEP 2434), the functional characteristic of comprising a TM2SF1 antibody variant thereof and a degrader molecule is insufficient to describe the genus.
Further, applicants have not shown possession of a representative number of species of heterobifunctional compounds. As noted above, some claim embodiments do not recite any structure and other embodiments state that the antibodies comprise CDRs comprising 75% sequence identity to a given sequence and heavy chain and light chain regions comprising 75% identity to a given sequence. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. Although the specification sets forth a correlation between the heterobifunctional compounds comprising the fully described anti-TM4SF1 antibodies and the degrader molecules Brd4 and BCL-XL and the claimed function(s), this correlation does not appear to be clearly present in the breadth of the claims. Therefore, only a few species have been described and the specification does not describe species that reflect the variation within 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).
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).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant 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 case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of anti-TM4SF1 by its function of binding TM4SF1, and/or a partial structure. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. 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.
The state of the art regarding modified Fc regions is discussed by Grevys et al J Immunology 194: 5497-5508, 2015) teaches that substitution of amino acids in the CH2 and CH3 domains, which are distally from C1q and FcgRs binding sites, may induce conformational changes or position shift of CH2 domain in glycosylated IgG, which may directly affect interaction with C1q and FcgRs, leading to unpredictable changes in the effector functions. For example, substitutions of M252 Y/S254T/T246E in human IgG1 Fc resulted in reduced binding to hFcγRIIa and more than 2-fold reduction in antibody dependent cytotoxicity (ADCC) (See page 5505). Thus, engineering of FcRn—IgG interaction may influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIlgG1 variants. 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-drag conjugate at the time the instant application was filed, and hence not in possession of method of using said antibody drug conjugate at the time the instant application was filed.
Applicant has provided little or no descriptive support beyond the mere presentation of generic or partially named structures to enable one of ordinary skill in the art to determine the actual structural composition of the claimed genus of heterobifunctional compounds. Although the prior art outlines art-recognized procedures for producing and screening for recombinant proteins this is not sufficient to impart possession of the genera of variant proteins to Applicant. Even if a few structurally identifiable composition components were described in the specification, they may not be sufficient, as the ordinary artisan would not necessarily immediately recognize how to put them together in such a way as to form a completely constructed heterobifunctional compound such that one would be able to distinguish it from the heterobifunctional compounds of the prior art. Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of heterobifunctional compounds as claimed.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed method which encompasses treating any cancer. 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).
Claims 126-143 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 heterobifunctional compound comprising an anti-TMSF1 antibodies selected from the group consisting of AGX-A01, AGX-A03, AGX-A04, AGX-A05, AGX-A07, AGX-A08, AGX-A09, AGX-A11, AGX-A07 H2v1L5v2, AGX-A07 H2L5 and a degrader molecule selected from the group consisting of Brd4, BCL-XL, and Ak2, does not reasonably provide enablement for all heterobifunctional compounds comprising all anti-TM4SF1 antibodies and all degrader molecules. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working samples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
(1) Nature of the invention and (6) Breadth of the claims
The nature of the invention is a heterobifunctional compound that comprises:
(a) an anti-TM4SF 1 antibody or an antigen binding fragment thereof;
(b) a degrader molecule; and
(c) a first linker L1 between the anti-TM4SF1 antibody and the degrader molecule wherein the degrader molecule comprises:
(i) a single-ligand molecule that directly interacts with a target protein to induce degradation of the target protein; or
(ii) a chimeric degrader molecule comprising a specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER); or
(iii) a single-ligand molecule that interacts with an E3 ubiquitin ligases to modulate substrate selectivity of the E3 ubiquitin ligase; or
(iv) a ubiquitin E3 ligase binding group (E3LB) and a target protein binding group (PB).
Therefore, the nature of the invention is a chemical case, wherein there is natural unpredictability in performance of certain species or sub- combination other than those specifically enumerated; see MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to make and use the claimed heterobifunctional compounds, with a reasonable expectation of success, because it would be not be predictable from the disclosure of any particular species what other species may or may not work; see MPEP 2164.03.
Although the instant claims are inclusive of the specific heterobifunctional compounds comprising full described anti-TM4SF1 antibodies and fully described degrader molecules, the claims are not limited to these compounds. The claims broadly encompass a vast genus of compounds comprising component parts that are not adequately described.
Regarding the anti-TM5SF1 antibody portion of the heterobifunctional compound, although the claims are inclusive of anti-TM5SF1 antibodies comprising a heavy chain comprising a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 8, 20, 32, 44, 56, 68, 80, 96, 118, 119, 120, or 121; a CDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 19, 31, 43, 55, 67, 79, 95, 116, or 117; and a CDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 18, 30, 42, 54, 66, 78, 94, or 115; and (b) a light chain comprising a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 26, 38, 50, 62, 74, 86, 110, 111, or 129; a CDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 25, 37, 49, 61, 73, 85, 109, or 128; and a CDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 24, 36, 48, 60, 72, 84, 107, 108, 124, 125, 126, or 127, the claims also include variants comprising CDR sequences that have at least 75% identity the aforementioned CDR sequences. The claims are also inclusive of the anti-TM5SF1 antibodies comprising a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 15, 27, 39, 51, 63, 75, 90, 92, 112, 114, 130, or 132, and a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 9, 21, 33, 45, 57, 69, 81, 97, 99, 101, 122, 131, or 133, as well are variants comprising heavy chain and light chain sequences that share 75% identity to the aforementioned sequences. Further compounding the breadth of the claims is that the antibody can further comprise a modified IgG Fc region, wherein the modified IgG Fc region comprises one or more substitutions at one or more positions selected from the group consisting of E233, L234, L235, G237, M252m S254, T250, T256. D265, N297, K322, P331, M428, and N434. Thus, the claims encompass an extremely large number of antibodies that have specific required functions. To give an idea of the breadth of the claims, CDR3 of the heavy chain must have at least 75% sequence identity to SEQ ID NO:8. SEQ ID NO:8 has 14 amino acids. To reach at least 75% identity, up to three amino acids can be varied at any position within the CDR. Mutating three sites out of fourteen residues results in 2,744 possible mutation site combinations. Leaving out the potential added complexity of substituting non-natural amino acids, substitutions at the sites can be selected from 19 other amino acids. Selecting three sites with 19 different amino acids gives over 6,859 possible combinations, and that is just for one set of substitution sites out of all the possible combinations. Therefore, there are thousands of possible antibodies when only considering the CDRs. Adding in further substitutions in the structural sequences attached to the CDRs will introduce further variation, producing millions of possible antibody sequence combinations. The specification discloses ten species within the instant claims scope and does not provide any guidance as to which amino acids can be varied while retaining the appropriate functions. 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. 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.
Regarding the degrader molecule of the heterobifunctional compound, while the claims are inclusive of heterobifunctional compounds comprising Brd4 and BCL-XL as the degrader component, the claims broadly encompass functionally defined degrader molecules of claims 126-128. The degrader has specific required functions; however, the specification does not provide any structure identifying information (e.g., the structure of the degrader molecule) such that one of skill in the art could readily envisage the degrader molecule of the heterobifunctional compound.
(5) The state of the prior art and (7) The predictability or unpredictability of the art
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.
The state of the art regarding modified Fc regions is discussed by Grevys et al J Immunology 194: 5497-5508, 2015) teaches that substitution of amino acids in the CH2 and CH3 domains, which are distally from C1q and FcgRs binding sites, may induce conformational changes or position shift of CH2 domain in glycosylated IgG, which may directly affect interaction with C1q and FcgRs, leading to unpredictable changes in the effector functions. For example, substitutions of M252 Y/S254T/T246E in human IgG1 Fc resulted in reduced binding to hFcγRIIa and more than 2-fold reduction in antibody dependent cytotoxicity (ADCC) (See page 5505). Thus, engineering of FcRn—IgG interaction may influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIlgG1 variants. 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-drag conjugate at the time the instant application was filed, and hence not in possession of method of using said antibody drug conjugate at the time the instant application was filed.
(6) The amount of direction or guidance by the inventor; (7) The existence of working examples
The specification discloses anti-TMSF1 antibodies named AGX-A01, AGX-A03, AGX-A04, AGX-A05, AGX-A07, AGX-A08, AGX-A09, AGX-A11, AGX-A07 H2v1L5v2, AGX-A07 H2L5. The specification teaches various exemplary degraders (Brd4, BCL-X