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 preliminary amendment filed 1/30/24 is acknowledged. Claims 1, 3-10, 15, 20, 24, 28-29, 36, 47, 48, and 49 have been amended. Claims 11-14, 16-19, 21-23, 25-27, 30-35, 37-46, and 50-59 have been canceled. Claims 1-10, 15, 20, 24, 28-29, 36, and 47-49 are pending and under examination.
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 1-10, 15, 20, 24, 28-29, 36, and 47-49 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 a multi-specific antigen-binding protein, comprising:
(a) a first antigen-binding portion that recognizes the first antigen, wherein the first antigen is a tumor-associated antigen (TAA);
(b) a second antigen-binding portion, wherein the second antigen-binding portion is an innate immune cell agonist; and
(c) a third antigen-binding portion that recognizes the third antigen, wherein the third antigen regulates the tumor microenvironment; wherein the positions of the second antigen-binding portion and the third antigen- binding portion are interchangeable.
The specification has provided trifunctional antibodies against CD24, NKP30 targets, and TGFβR2, constructed according to the six structures of figures 1-6, which were named DNT-A to DNT-F. The specification teaches that in these species, the first antigen-binding portion targets CD24, the second antigen-binding portion targets NKP30 in the form of VHH; and the third antigen-binding portion targets TGF-β in the form of TGF-β receptor.
The specification teaches that trifunctional antibodies against vlaudin18.2, NKP30 targets, and TGF-βR2, which were named CNT-A to CNT-F. The specification teaches that in these species, the first antigen-binding portion targets Claudin18.2; the second antigen-binding portion targets NKP30 in the form of VHH; and the third antigen-binding target portion targets TGFβ in the form of TGF-β receptor.
Although the instant claims are inclusive of multispecific antigen-binding proteins comprising the specifically defined antibody and VHH sequences set forth in the specification, the claims are also inclusive of trifunctional antibodies that are defined solely by the function of binding to a tumor antigen, binding to an innate immune cell agonist, and binding to an antigen that regulations the tumor microenvironment. The claims state that the tumor-associated antigen is selected from the group consisting of: GPC3, CD19, CD20 (MS4A1), CD22, CD24, CD30, CD33, CD38, CD40, CD123, CD133, CD138, CDK4, CEA, Claudin6, Claudin18.2, CCR8, AFP, ALK, B7H3, BAGE protein, BCMA, BIRC5 (survivin), BIRC7, (3-catenin, brc-abl, BRCA1, BORIS, CA9, CA125, carbonic anhydrase IX, caspase-8, CALR, CCR5, NA17, NKG2D, NY-BR1, NY- BR62, NY-BR85, NY-ESO1,OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1, PRLR, PRAME, PSMA (FOLH1), RAGE proteins, cyclin-B1, CYP1B1, EGFR, EGFRvIII, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EpCAM, EphA2, Fra-1, FOLR1, GAGE protein, GD2, GD3, GloboH, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras, HLA/MAGE-A3, hTERT, IL13Ra2, LMP2, i-Light, LeY, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-6, MAGE- 12, MART-1, mesothelin, ML-IAP, MOv-y, Muc1, Muc2, Muc3, Muc4, MucS, Muc16, MUM1, Ras, RGS5, Rho, ROR1, SART-1, SART-3, STEAPi, STEAP2, TAG-72, TGF-3, TNFR2, TMPRSS2, Thom-Knott's antigen, TRP-1, TRP-2, tyrosinase, and urolytic protein-3, 5T4. The claims state that the second antigen is selected from the group consisting of: NKP30, NKP46, CD16, NKP44, CD244, CD226, NKG2E, NKG2D, NKG2C, and KIR. The claims state that the third antigen is selected from TGFβ, CD39, CD73, A2aR, IL-4, IL-6, IL-10, IL-13, IL-17, IL-37, PD-1, PD-L1, VEGF, ANG2, CCL2, CCL17, CCL22, CCL28, CSF1, CXCL12, GM-CSF. Further adding to the breadth of the claims is that the claims state that the antigen-binding portion has various formats and is one of Fab, scFab, F(ab')2, Fv, dsFv, scFv, VH or VL structural domain, or a VHH. Therefore, there are hundreds if not thousands of multispecific antigen-binding proteins encompassed by the claims. These multispecific antigen-binding proteins have no correlation between their structure and 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. 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 binding proteins claimed only by a functional characteristic and/or a partial structure.
Thus, the genus of multispecific antigen-binding proteins 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 multispecific antigen-binding proteins without adequate descriptions of its component parts or overall makeup. The generically claimed first antigen binding portion, second antigen binding portion, and third antigen binding portion 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 binding proteins recited in the claims. For instance, without knowing the target and structure of the claimed first antigen binding portion, one would not be able to adequately describe the claimed binding protein. Likewise, one would need the structure of the second antigen binding site to adequately describe the binding protein. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of multispecific antigen-binding proteins because, inter alia, the specification does not disclose a correlation between the necessary structure of the multispecific antigen-binding protein 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 multispecific antigen-binding protein may generically describe the binding proteins' function, it does not describe the multispecific antigen-binding protein itself. A definition by function does not suffice to define the genus because it is only an indication of what the multispecific antigen-binding protein 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 multispecific antigen-binding proteins is highly variable (i.e., each multispecific antigen-binding protein would necessarily have a unique structure; see MPEP 2434), the functional characteristics of recognizing a TAA, being an innate immune cell agonist, and regulating the tumor microenvironment is insufficient to describe the genus.
Further, applicants have not shown possession of a representative number of species of multispecific antigen-binding protein. As noted above, the claims do not recite any target or structure for the multispecific antigen-binding proteins. The claims generically recite wherein the antigen-binding portion is a full-length antibody, an antibody fragment comprising a VH and/or VL domain, Fab, scFab, F(ab')2, Fv, dsFv, scFv, VH or VL structural domain, or a VHH. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. Although the specification sets forth a correlation between the trifunctional antibodies 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 multispecific antigen-binding proteins 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 multispecific antigen-binding proteins, 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).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 3, 4, 29, and 47-49 are is rejected 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.
Claim 3 recites the limitation "the second antigen protein" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 3 depends from claim 2 and there is no recitation of a second antigen binding protein in claim 2. Clarification and/or correction is required.
Claims 4 and 49 recite the limitation "third antigen". There is insufficient antecedent basis for this limitation in the claim. Claims 4 and 49 depend from claim 2 and there is no recitation of a third antigen in claim 2.
Claim 29 recites the third antigen-binding portion is located between any one of the VH, CH1 domain, CH2 domain, and CH3 domain of the first antigen-binding portion and/or the second antigen-binding portion. Given that the claim recites the third portion is between any one of the recited structures, one of skill in the art would not be apprised of the exact location of the third antigen-binding portion. Therefore, the scope of the claim is ambiguous and one of skill in the art would not be apprised of the metes and bounds of the claim.
Claim 47 recites CD20 (MS4A1), BIRC5 (survivin), and PMSA(FOLH1). Although parenthesis may be appropriate when defining an abbreviation or acronym, the inclusion of parentheses for anything else (e.g., CD20 (MS4A1), BIRC5 (survivin), PMSA(FOLH1)), raises uncertainty as to whether the feature in the parentheses is optional or always present. Clarification and/or correction is required.
Claim 48 recites the limitation "the second antigen". There is insufficient antecedent basis for this limitation in the claim. Claim 48 depends from claim 4 and there is no recitation of a second antigen in claim 4. Clarification and/or correction is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-8, 10, 36, and 47-50 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Chang et al. (WO 2019157332 A1, published August 15, 2019).
The instant claims are drawn to a multi-specific antigen-binding protein, comprising:
(a) a first antigen-binding portion that recognizes the first antigen, wherein the first antigen is a tumor-associated antigen (TAA);
(b) a second antigen-binding portion, wherein the second antigen-binding portion is an innate immune cell agonist; and
(c) a third antigen-binding portion that recognizes the third antigen, wherein the third antigen regulates the tumor microenvironment; wherein the positions of the second antigen-binding portion and the third antigen- binding portion are interchangeable.
Chang et al. teach a multi-specific binding protein comprising: (a) a first antigen-binding site that binds NKG2D; (b) a second antigen binding site that binds a tumor-associated antigen; and (c) a third antigen binding site that binds CD16 (See paragraph 0007). Chang et al. teach that the antigen-binding sites each incorporate an antibody heavy chain variable domain and an antibody light chain variable domain (e.g. arranged as in an antibody, or fused together to from an scFv), or one or more of the antigen-binding sites may be a single domain antibody, such as a VHH antibody like a camelid antibody or a VNAR antibody (See paragraph 0020). Chang et al. teach wherein the second antigen-binding portion (i.e., Fab binding to antigen 2) is fused to the N-terminus of the heavy chain of the first antigen-binding portion (i.e., HC of Fab that binds to antigen 1) (See paragraphs 0107 and 0150). Chang et al. teach wherein the multispecific binding protein comprising a first Fc region and a second Fc region. Change et al. teach that the first Fc domain and second Fc domain together are able to bind to CD16 (See figure 1 and paragraph 0136). Chang et al. teach that the TAA is CD33, CD19, CD22, BCMA, PSMA, mesothelin (MSLN), ROR1, WT1, L1CAM, MUC16, or LeY (See paragraphs 0187 and 0255). Chang et al. teach that the tumor-associated antigen can be selected from the group consisting of HER2, CD20, CD33, B-cell maturation antigen (BCMA), EpCAM, CD2, CD19, CD25, CD30, CD38, CD40, CD52, CD70, CLL1/CLEC12A, FLT3, EGFR/ERBB1, IGF1R, HER3/ERBB3, HER4/ERBB4, MUC1, cMET, SLAMF7, PSCA, MICA, MICB, TRAILR1, TRAILR2, MAGE- A3, B7.1, B7.2, CTLA4, HLA-E, and PD-L1 (See paragraph 0020). Regarding claims 2-4, the claims recite functional limitations. The prior art teaches that specific antigen binding portion required by the claim, and thus, the prior art structure would inherently possess the claimed function(s). Thus, Chang et al. anticipate the claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-10, 15, 20, 24, 28-29, 36, and 47-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 16, 21, 25, 29-30, 48-49, and 51 of copending Application No. 18/293,515 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a a multi-specific antigen-binding protein, comprising: (a) a first antigen-binding portion that recognizes the first antigen, wherein the first antigen is a tumor-associated antigen (TAA); (b) a second antigen-binding portion, wherein the second antigen-binding portion is an innate immune cell agonist; and (c) a third antigen-binding portion that recognizes the third antigen, wherein the third antigen regulates the tumor microenvironment; wherein the positions of the second antigen-binding portion and the third antigen- binding portion are interchangeable. The ‘515 claims teach wherein the antigen targeting tumorigenesis or progression is a tumor- associated antigen (TAA) and/or a tumor-specific antigen (TSA). The ‘515 claims teach wherein the innate immune cell agonist is an NK cell agonist and/or a y6T cell agonist. The ‘515 claims teach wherein the second antigen-binding protein recognizes the second antigen expressed on the innate immune cells, and the second antigen-binding protein activates the innate immune cells after binding to the second antigen. The ‘515 claims teach wherein the third antigen is a pro-angiogenic factor. The ‘515 claims teach wherein the first antigen-binding portion and/or the second antigen- binding portion and/or the third antigen-binding portion is a full-length antibody comprising two heavy chains and two light chains. The ‘515 claims teach wherein the first antigen-binding portion and/or the second antigen- binding portion and/or the third antigen-binding portion is an antibody fragment comprising a heavy chain variable domain (VH) and/or a light chain variable domain (VL). The ‘515 claims teach wherein the first antigen-binding portion and/or the second antigen-binding portion and/or the third antigen-binding portion is one of Fab, scFab, F(ab')2, Fv, dsFv, scFv, VH or VL structural domain. The ‘515 claims teach wherein the first antigen-binding portion and/or the second antigen- binding portion and/or the third antigen-binding portion is a single-domain antibody (VHH). The ‘515 claims teach wherein the first antigen-binding portion and/or the second antigen- binding portion and/or the third antigen-binding portion is a receptor for an antigen. The ‘515 claims teach wherein the second antigen-binding portion is fused to the N- terminus and/or C-terminus of one of the heavy chains of the first antigen-binding portion. The ‘515 claims teach wherein the second antigen-binding portion is fused to the N- terminus and/or C-terminus of one of the light chains of the first antigen-binding portion. The ‘515 claims teach wherein the second antigen-binding portion is fused to the N- terminus and/or C-terminus of both heavy chains of the first antigen-binding portion. The ‘515 claims teach wherein the second antigen-binding portion is fused to the N- terminus and/or C-terminus of both light chains of the first antigen-binding portion. The ‘515 claims teach wherein the third antigen-binding portion replaces one or more binding units of: Fab region or Fv region or VH, CH1 domain, CH2 domain, or CH3 domain of the first antigen-binding portion, and/or the second antigen-binding portion. The ‘515 claims teach wherein the third antigen-binding portion is located between any one of: VH, CH1 domain, CH2 domain, and CH3 domain of the first antigen-binding portion and/or the second antigen-binding portion. The ‘515 claims teach wherein the tumor-associated antigen is selected from the group consisting of: GPC3, CD19, CD20 (MS4A1), CD22, CD24, CD30, CD33, CD38, CD40, CD123, CD133, CD138, CDK4, CEA, Claudin6, Claudin18.2, CCR8, AFP, ALK, B7H3, BAGE protein, BCMA, BIRC5 (survivin), BIRC7, (3-catenin, brc-abl, BRCA1, BORIS, CA9, CA125, carbonic anhydrase IX, caspase-8, CALR, CCR5, NA17, NKG2D, NY-BR1, NY- BR62, NY-BR85, NY-ESO1,OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1, PRLR, PRAME, PSMA (FOLH1), RAGE proteins, cyclin-B1, CYP1B1, EGFR, EGFRvIII, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EpCAM, EphA2, Fra-1, FOLR1, GAGE protein, GD2, GD3, GloboH, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras, HLA/MAGE-A3, hTERT, IL13Ra2, LMP2, i-Light, LeY, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-6, MAGE- 12, MART-1, mesothelin, ML-IAP, MOv-y, Muc1, Muc2, Muc3, Muc4, Muc5, Muc16, MUM1, Ras, RGS5, Rho, ROR1, SART-1, SART-3, STEAPI, STEAP2, TAG-72, TGF-3, TNFR2, TMPRSS2, Thom-Knott's antigen, TRP-1, TRP-2, tyrosinase and urolytic protein-3, 5T4, hepatitis B surface antigen (HBSAG), tissue polypeptide antigen (TPA), carbohydrate antigen 153 (CA153), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 724 (CA724), carbohydrate antigen 242 (CA242), carbohydrate antigen 50 (CA50), CYFRA21-1 (Cy211), neuron specific enolase (NSE), prostate-specific antigen (PSA), human chorionic gonadotropin (HCG), thyroglobulin (TG), ferritin (SF), (2-microglobulin (p2-MG), squamous cell antigen (SCC). The ‘515 claims teach wherein the second antigen is selected from the group consisting of: NKP30, NKP46, CD16, NKP44, CD244, CD226, NKG2E, NKG2D, NKG2C, and KIR. The ‘515 claims teach wherein the second antigen is selected from the group consisting of: Vδ1T, V82T, Vδ3T, γδTreg, γδT17, IFN-γ⁺γδT. The ‘515 claims teach wherein the third antigen is selected from the group consisting of: EGF, FGF, FGF, FGF-α, FGF-ß, VEGF, VEGFR, HDGF, HGF, HGFK1, NRP-1, ANG, Ang1, Ang2, PDGF, PDGFR, PIGF, TGF-α, TGF-ß, TGF-β receptor, CD31, CD105, MCP-1, COX- 2, AC133, Id2/Id3, IL-1α, IL-6, IL-1ß, IL-8, CXCL5, MMP, and THBS, AREG, ET-1, AAMP, AGGFI, AMOT, ANGLPTL3, ANGPTL4, BTG1, NOS3, TNFSF12, VASH2, integrinavß3, α5ß1, VE-cadherin, leptin, heparin, plasminogen activator, and plasminogen activator inhibitor-1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-10, 15, 20, 24, 28-29, 36, and 47-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 15, 20, 25, 30, 35, 39-42, and 46-48 of copending Application No. 18569320 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a a multi-specific antigen-binding protein, comprising: (a) a first antigen-binding portion that recognizes the first antigen, wherein the first antigen is a tumor-associated antigen (TAA); (b) a second antigen-binding portion, wherein the second antigen-binding portion is an innate immune cell agonist; and (c) a third antigen-binding portion that recognizes the third antigen, wherein the third antigen regulates the tumor microenvironment; wherein the positions of the second antigen-binding portion and the third antigen- binding portion are interchangeable.
The ‘320 claims teach wherein the second antigen-binding portion specifically recognizes a second antigen expressed on NK cells, and the second antigen-binding portion activates the NK cells upon binding to the second antigen. The ‘320 claims teach wherein the first antigen-binding portion and/or the second antigen-binding portion is a full-length antibody comprising two heavy chains and two light chains. The ‘320 claims teach wherein the first antigen-binding portion and/or the second antigen-binding portion is a full-length antibody comprising two heavy chains and two light chains. The ‘320 claims teach wherein the first antigen-binding portion and/or the second antigen-binding portion is an antibody fragment comprising a heavy chain variable domain (VH) and/or a light chain variable domain (VL). The ‘320 claims teach wherein the first antigen-binding portion and/or the second antigen-binding portion is one of Fab, scFab, F(ab')2, Fv, dsFv, scFv, VH or VL structural domain. The ‘320 claims teach wherein the first antigen-binding portion and/or the second antigen-binding portion is a single-domain antibody (VHH). The ‘320 claims teach wherein the third functional portion is located between the CH1 structural domain and the CH2 structural domain, or the third functional portion is located between the CH2 structural domain and the CH3 structural domain, or the third functional portion is located between the VH structural domain and the CH1 structural domain, of the first antigen-binding portion and/or the second antigen-binding portion. The ’320 claims teach wherein the third functional portion replaces one or more of: the CH1 structural domains, the CH2 structural domains, the CH3 structural domains of the heavy chain of the first antigen-binding portion, and/or the second antigen-binding portion. The ‘320 claims teach wherein the third functional portion is fused to the C-terminus of at least one heavy chain of the first antigen-binding portion. The ‘320 claims teach wherein the third functional portion is fused to the N-terminus of at least one heavy chain of the first antigen-binding portion. The ‘320 claims teach wherein the third functional portion is fused to the C-terminus of at least one light chain of the first antigen-binding portion. The ‘320 claims teach wherein the third functional portion is fused to the N-terminus of at least one light chain of the first antigen-binding portion. The ‘320 claims teach wherein the multispecific antigen-binding protein comprises a first Fc region and a second Fc region. The ‘320 claims teach wherein the VH and VL of the first antigen-binding portion and/or the second antigen-binding portion are interchanged. The ‘320 claims teach wherein the CL and CH1 of the first antigen-binding portion and/or the second antigen-binding portion are interchanged. The ‘320 claims teach wherein CH3 of the first Fc region is replaced by CL or CH1, and CH3 of the second Fc region is replaced by CL or CH1. The ‘320 claims teach wherein the heavy chain and/or the Fc fragment of the first antigen- binding portion and/or the second antigen-binding portion comprises one or more amino acid substitutions, and the substitutions form an ionic bond between the heavy chain and the Fc fragment. The ‘320 claims teach wherein the tumour-associated antigen is selected from the group consisting of: GPC3, CD19, CD20 (MS4A1), CD22, CD24, CD30, CD33, CD38, CD40, CD123, CD133, CD138, CDK4, CEA, Claudin18.2, AFP, ALK, B7H3, BAGE protein, BCMA, BIRC5 (survivin), BIRC7, (3-catenin, brc-abl, BRCA1, BORIS, CA9, CA125, carbonic anhydrase IX, caspase-8, CALR, CCR5, NA17, NKG2D, NY-BR1, NY-BR62, NY- BR85, NY-ESO1,OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1, PRLR, PRAME, PSMA (FOLH1), RAGE proteins, cyclin-B1, CYP1B1, EGFR, EGFRvIII, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EpCAM, EphA2, Fra-1, FOLR1, GAGE protein, GD2, GD3, GloboH, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras, HLA/MAGE-A3, hTERT, IL13Ra2, LMP2, -Light, LeY, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-6, MAGE-12, MART-1, mesothelin, ML-IAP, MOv-y, Muc1, Muc2, Muc3, Muc4, Muc5, Muc16, MUM1, Ras, RGS5, Rho, ROR1, SART-1, SART-3, STEAPI, STEAP2, TAG-72, TGF-(3, TMPRSS2, Thom-Knott's antigen, TRP-1, TRP-2, tyrosinase, and urolytic protein-3, 5T4. The ‘320 claims teach wherein the second antigen is selected from the group consisting of: NKP30, NKP46, CD16, NKP44, CD244, CD226, NKG2E, NKG2D, NKG2C, KIR. The ’320 claims teach wherein the cytokine and/or cytokine receptor is selected from the group consisting of: IL-1,IL-2, IL-2 Ra, IL-2 R(3,IL-3, IL-3 Ra, IL-4, IL-4 Ra, IL-5, IL-5 Ra, IL-6, IL-6 Ra, IL-7, IL-7 Ra, IL-8, IL-9, IL-9 Ra, IL-10, IL-lORi,IL-10R2, IL-11, IL-11 Ra, IL-12, IL-12 Ra, IL-12 R(32, IL-12 R(31,IL-13, IL-13 Ra, IL-13 Ra2,IL-14, IL-15, IL-15Ra sushi, IL-16, IL-17, IL-18, IL-19, IL-20, IL-20R1, IL-20R2, IL-21, IL-21 Ra, IL-22, IL-23, IL-23R, IL-27 R, IL-31 R, G-CSF-R, LIF-R, OSM-R, GM-CSF- R, R3c, Ryc, TSL-PR, EB13, CLF-1, CNTF- Ra, gp130, Leptin-R, PRL-R, GH-R, Epo-R, Tpo-R, IFN-XR1, IFN- XR2, IFNR1, IFNR2.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Status
No claims are allowed.
Conclusion
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/SANDRA CARTER/ Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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