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 3/11/26 are acknowledged. Claims 1, 3, 5, 6, 7, 9, 10 have been amended. Claims 16-21 have been added. Claims 1-11 and 15-21 are pending and under examination.
Withdrawn Rejections
The rejection of claims 1-11 and 15 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 protein complex selected from the group consisting of variant 1, diabody split CH2 comprising a PCA according to SEQ ID NO: 11 and a PCB according to SEQ ID NO: 12; variant 2: A DVD-Fab split CH2 having a PCA according to SEQ ID NO: 13 and a PCB according to SEQ ID NO: 14; variant 3: A CODV-Fab split CH2 comprising a PCA according to SEQ ID NO: 15 and a PCB according to SEQ ID NO: 16; variant 4: A splite diabody comprising a PCA according to SEQ ID NO: 17 and a PCB according to SEQ ID NO: 18; variant 5: A splite diabody comprising a PCA according to SEQ ID NO: 19 and a PCB according to SEQ ID NO: 20; variant 6: A splite diabody comprising a PCA according to SEQ ID NO: 17 and a PCB according to SEQ ID NO: 20; variant 7: A splite diabody comprising a PCA according to SEQ ID NO: 19 and a PCB according to SEQ ID NO: 18; variant 8: A diabody split CH2 tetravalent bispecific antibody comprising two PCAs according to SEQ ID NO: 11 and two PCBs according to SEQ ID NO: 21; variant 9: A DVD split CH2 tetravalent bispecific antibody comprising two PCAs according to SEQ ID NO: 13 and two PCBs according to SEQ ID NO: 22; variant 10: A CODV split CH2 tetravalent bispecific antibody comprising two PCAs according to SEQ ID NO: 15 and two PCBs according to SEQ ID NO: 23; variant 11: A split CH2 bivalent bispecific antibody having a PCA according to SEQ ID NO: 25 and a PCB according to SEQ ID NO: 26; variant 12: A split CH2 bivalent bispecific antibody comprising a PCA according to SEQ ID NO: 29 and a PCB according to SEQ ID NO: 28; variant 13: A diabody split IgA CH2 (Figure 21) comprising a PCA according to SEQ ID NO: 41 and a PCB according to SEQ ID NO: 42; variant 14: A diabody split IgD CH2 comprising a PCA according to SEQ ID NO: 43 and a PCB according to SEQ ID NO: 44; variant 15: A diabody split IgE CH3 comprising a PCA according to SEQ ID NO: 45 and a PCB according to SEQ ID NO: 46; variant 16: A diabody split IgE CH2 comprising a PCA according to SEQ ID NO: 47 and a PCB according to SEQ ID NO: 48, does not reasonably provide enablement for all protein complexes comprising at least two polypeptide chains (PCA and PCB), wherein each PCA and PCB comprises a heterodimerization domain (HDA and HDB), is withdrawn. See paragraph 8, page 14.
The rejection of claims 6 and 9 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in light of Applicant’s amendment thereto. See paragraph 10, page 22 of the previous Office action.
The rejection of claims 1, 3, 4, 8, and 9 under 35 U.S.C. 102(a)(1) as being anticipated by Davis et al. (Protein Engineering, Design & Selection, 23(4):195-202, 2010), is withdrawn in light of Applicant’s amendment thereto. See paragraph 16, page 23 of the previous Office action.
New Rejections 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 1-11 and 15-21 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 instant claims are drawn to a protein complex comprising at least two polypeptide chains A (PCA) and B (PCB), wherein PCA comprises a heterodimerization domain A (HDA) and PCB comprises a heterodimerization domain B (HDB) that bind to each other and wherein one heterodimerization domain comprises or consists of two N-terminal B-strands of an immunoglobulin (Ig) domain (N-B) and does not comprise one or more C-terminal β srands of an Ig domain and the other heterodimerization domain comprises or consists of two C-terminal B-strands of an Ig domain (C-B) and does not comprise one or more N-terminal β-strands of an Ig domain.
The specification teaches bispecific antibodies being DVD-Fab, CODV-Fab, diabodies and bivalent bispecific antibodies having as heterodimerization domains split CH2 domains. The examples all relate to bispecific IL4/IL13 antibodies. The specification discloses exemplary antibodies or derivatives thereof: variant 1, diabody split CH2 comprising a PCA according to SEQ ID NO: 11 and a PCB according to SEQ ID NO: 12; variant 2: A DVD-Fab split CH2 having a PCA according to SEQ ID NO: 13 and a PCB according to SEQ ID NO: 14; variant 3: A CODV-Fab split CH2 comprising a PCA according to SEQ ID NO: 15 and a PCB according to SEQ ID NO: 16; variant 4: A splite diabody comprising a PCA according to SEQ ID NO: 17 and a PCB according to SEQ ID NO: 18; variant 5: A splite diabody comprising a PCA according to SEQ ID NO: 19 and a PCB according to SEQ ID NO: 20; variant 6: A splite diabody comprising a PCA according to SEQ ID NO: 17 and a PCB according to SEQ ID NO: 20; variant 7: A splite diabody comprising a PCA according to SEQ ID NO: 19 and a PCB according to SEQ ID NO: 18; variant 8: A diabody split CH2 tetravalent bispecific antibody comprising two PCAs according to SEQ ID NO: 11 and two PCBs according to SEQ ID NO: 21; variant 9: A DVD split CH2 tetravalent bispecific antibody comprising two PCAs according to SEQ ID NO: 13 and two PCBs according to SEQ ID NO: 22;
variant 10: A CODV split CH2 tetravalent bispecific antibody comprising two PCAs according to SEQ ID NO: 15 and two PCBs according to SEQ ID NO: 23; variant 11: A split CH2 bivalent bispecific antibody having a PCA according to SEQ ID NO: 25 and a PCB according to SEQ ID NO: 26; variant 12: A split CH2 bivalent bispecific antibody comprising a PCA according to SEQ ID NO: 29 and a PCB according to SEQ ID NO: 28; variant 13: A diabody split IgA CH2 (Figure 21) comprising a PCA according to SEQ ID NO: 41 and a PCB according to SEQ ID NO: 42; variant 14: A diabody split IgD CH2 comprising a PCA according to SEQ ID NO: 43 and a PCB according to SEQ ID NO: 44; variant 15: A diabody split IgE CH3 comprising a PCA according to SEQ ID NO: 45 and a PCB according to SEQ ID NO: 46; variant 16: A diabody split IgE CH2 comprising a PCA according to SEQ ID NO: 47 and a PCB according to SEQ ID NO: 48.
Although the instant claims are inclusive of protein complexes comprising the specifically defined PCA and PCB sequences set forth in the specification, the claims are also encompass protein complexes comprising generically defined polypeptide chains (PCA and PCB) that are defined solely by the presence of a heterodimerization domain A and B (HDA and HDB) that must bind to each other. In some claim embodiments, the HDA comprises the sequence of SEQ ID NO: 1 or a variant thereof comprising 80-98% sequence identity to SEQ ID NO: 1, and the HBD comprises the sequence of SEQ ID NO: 2 or a variant thereof comprising 80-98% sequence identity to SEQ ID NO: 2. The claims further specify that the protein complex comprises one or more antigen binding sites within the PCA and/or PCB. The claims further state that the PCA and/or PCB comprises one or more further homo and/or heterodimerization domain C. Thus, the claims encompass an extremely large number of protein complexes that have specific required functions. To give an idea of the breadth of the claims, the HDA sequence of must have at least 80% sequence identity to SEQ ID NO: 1. SEQ ID NO: 1 has 49 amino acids. To reach at least 80% identity, up to 9 amino acids can be varied at any position within the sequence. Mutating 9 sites out of 49 results in 1.62x1015 possible mutation site combinations. Leaving out the potential added complexity of substituting non-natural amino acids, substitutions at the site can be selected from 19 other amino acids. Selecting 9 sites with 19 different amino acids gives over 3.23x1011 possible combinations, and that is just for one set of substitution sites out of all the possible combinations. Therefore, there are millions of possible protein complexes when only considering the polypeptide chains. Adding in further substitutions in the structural sequences attached to the protein complex will introduce further variation, producing millions of possible protein complex sequence combinations. The specification discloses 16 species within the instant claim scope; however, the specification does not provide any guidance as to which amino acids can be varied while retaining the appropriate functions. The exemplary protein complexes have various antibody formats (e.g., diabody, DVD, CODV-Fab, etc.). 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.
Thus, the genus of protein complexes is extremely broad because the claims recite generic and incompletely described components. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed protein complexes without adequate descriptions of its component parts or overall makeup. The generically claimed PCA and PCB, and variants thereof, do not 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 protein complexes recited in the claims. For instance, without knowing the structure of the claimed PCA and PCB, one would not be able to adequately describe the claimed protein complex. Likewise, one would need the structure of the antigen binding site to adequately describe the protein complex. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of protein complexes because, inter alia, the specification does not disclose a correlation between the necessary structure of the protein complex 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 protein complex may generically describe the proteins’ function, it does not describe the protein complex 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 protein complexes is highly variable (i.e., each protein complex would necessarily have a unique structure; see MPEP 2434), the functional characteristic of comprising a PCA, PCB, an HDA and HDB that bind to each other, and an antigen binding site 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 protein complex comprises a PCA comprising a sequence that is 80% identical to SEQ ID NO:1 and a PCB comprising a sequence that is 80% identical to SEQ ID NO:2. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. Although the specification sets forth a correlation between the variants 1-16 protein complexes comprising fully defined sequences, 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 protein complexes by a function 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 protein complexes, 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.
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 protein complexes. 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 protein complex such that one would be able to distinguish it from the protein complexes 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 protein complexes 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).
Applicant’s Arguments
Applicant argues that the split Ig domain approach is a platform technology that does not depend on the presence of antigen binding domain. Applicant argues that the specification provides various binding proteins as examples of the claimed protein complexes to show that the split Ig domains can be placed at various different positions within the protein complexes: at the C- terminus adjacent to a variable domain or a CL or CH1 domain, or between two domains, such as between two variable domains, between a variable domain and a CH2 domain, or between a CH1 and a CH2 domain. Applicant argues that the examples provided in the specification demonstrate that the heterodimerization domains recited in the present claims can be employed in various protein complexes of different sizes and domain architecture. Applicant argues that although antigen binding proteins are used as examples of the claimed protein complexes to demonstrate the usefulness of the split Ig domain approach, this platform technology can also be used with other non-antigen binding proteins. Applicant argues that variable domains of different antigen specificity do not significantly differ in their overall shape, and any variable domains can be combined with the heterodimerization domains recited in the present claims. Applicant argues that in many of the exemplary protein complexes provided in the specification, the split Ig domains are not even located adjacent to the variable domains. Applicant argues that the specificity for IL-4 and IL-13 is not a necessary feature for the presently claimed subject matter, and the claims should not be so limited.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive. The claims encompass a vast genus of protein complexes that are not adequately described. The claims recite generic descriptions for the component parts of the complex. For instance, although some claim embodiments recite a partial structure for the HDA and/or HDB, this is not sufficient to describe the complete protein complexes. As noted above, the claims state that the HDA comprises the sequence of SEQ ID NO: 1 or a variant thereof comprising 80-98% sequence identity to SEQ ID NO: 1, and the HBD comprises the sequence of SEQ ID NO: 2 or a variant thereof comprising 80-98% sequence identity to SEQ ID NO: 2. To give an idea of the breadth of the claims, the HDA sequence of must have at least 80% sequence identity to SEQ ID NO: 1. SEQ ID NO: 1 has 49 amino acids. To reach at least 80% identity, up to 9 amino acids can be varied at any position within the sequence. Mutating 9 sites out of 49 results in 1.62x1015 possible mutation site combinations. Leaving out the potential added complexity of substituting non-natural amino acids, substitutions at the site can be selected from 19 other amino acids. Selecting 9 sites with 19 different amino acids gives over 3.23x1011 possible combinations, and that is just for one set of substitution sites out of all the possible combinations. Therefore, there are millions of possible protein complexes when only considering the polypeptide chains. Adding in further substitutions in the structural sequences attached to the protein complex will introduce further variation, producing millions of possible protein complex sequence combinations. The specification discloses 16 species within the instant claim scope; however, the specification does not provide any guidance as to which amino acids can be varied while retaining the appropriate functions. The exemplary protein complexes have various antibody formats (e.g., diabody, DVD, CODV-Fab, etc.). Even considering just the HDA and HBA, considerable variation exists, well beyond the species disclosed in the specification.
The specification does not describe any relevant, identifying characteristics, such as structure, i.e., amino acid sequences of the PCA and PCB comprising a heterodimerization domain A and B, that correlate to binding or structure common to members of the genus, sufficient to show possession of the claimed genus. Thus, one of skill in the art cannot "visualize or recognize" most members of the genus.
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 protein complexes. 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 protein complex such that one would be able to distinguish it from the protein complexes 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 protein complexes as claimed.
Claim Status
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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Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa L. Ford can be reached at (571)272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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