DETAILED ACTION
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 response received September 4, 2026 is acknowledged.
Claims 2, 5, 9, 12, 15, 18, 25, and 27-29 have been canceled.
Claims 1, 3, 4, 6-8, 10, 11, 13, 14, 16, 17, 19-24, 26, and 30 are pending in the instant application.
Applicant’s election without traverse of the invention of group I, drawn to multispecific binding polypeptides comprising single domain antibodies in the reply filed on September 4, 2026 is acknowledged.
Claims 21-23 and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 September 4, 2026.
Claims 1, 3, 4, 6-8, 10, 11, 13, 14, 16, 17, 19, 20, 24, and 26 are under examination in this office action.
Information Disclosure Statement
The IDS forms received 10/6/2023, 2/15/2024, 4/10/2024, 12/16/2024, 1/27/2025, and 7/30/2026 are acknowledged and the references cited therein have been considered.
Claim Rejections - 35 USC § 112
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.
Claims 4, 8, 11, 14, 16, and 17 are 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.
Regarding claim 4, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Specifically, in claim 4 a genus of antibodies are initially claimed via recitation of multiple sequence for each CDR position, with the end of the claim then specifying “preferably” wherein the CDRs are an exact group recited by SEQ ID number. Thus, how is the claim to be interpreted? Are the “preferably” sequences simply examples of what is encompassed by the claimed genus and thus do NOT need to be satisfied to meet the recited claim limitations? If so, they should be deleted as exemplification is not permitted. See again MPEP 2173.05(d). Alternatively if they are limitations that must be met, why does the claim initially appear to indicate other sequences are possible to meet the limitations of the claim when they are in fact not what is being claimed? Deletion of either the larger antibody genus OR the “preferably” species is very strongly suggested. Note this same issue of the “preferable” language identifying a species with the larger recited genus is present in all of the other claims identified as part of this rejection (i.e. 8, 11, 14, 16, and 17), and the suggested resolution is the same, namely delete the larger genus or delete the “preferable” species.
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, 3, 4, 6-8, 10, 11, 13, 14, 16, 17, 19, 20, 24, and 26 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.
Applicant has broadly claimed immunoglobulin single variable domain (ISVD) polypeptides that minimally comprise three ISVD, the first binding an MMP, the second binding an ADAMTS, and the third binding Aggrecan. The broadest claims recite no specific structure which is responsible for the function of binding the recited antigens, while dependent claims recite different levels of structure, such as complete CDRs or VHH domains which are identified by SEQ ID number, although such claims also typically recite that mutations can be present, either by way of specifying a number of mutations such as is done in claim 4 for example, or by way of percent identity limitations as can be seen in claim 16 for example.
To support such breadth, the instant specification discloses that the anti-MMP13 ISVD named 62C02, the anti-ADAMTS5 ISVD clone named 02F03, and the anti-aggrecan ISVD named 114F08 were obtained following a large amount of screening (see working examples 1-3). Example 4 indicates that 62C02, 02F03, and 114F08 were joined together in various orientations and copy numbers in order to generate fusion polypeptides specific for MMP13, ADAMTS5, and aggrecan, with such constructs being tested for binding activity against human, monkey, and rat antigenic targets in example 5. The synthesized fusion protein are also disclosed as having been tested in in vitro model systems of collagen degradation (examples 6-9) as well as in vivo in rats (examples 10-14). No data appears to be provided concerning mutagenesis of 62C02, 02F03, and 114F08 or the structure of other ISVD that bind MMP13, ADAMTS5, or aggrecan. No data concerning the synthesis of fusion polypeptides which bind other antigens within genera recited in claim 1, such as a generic MMP or a generic ADAMTS appear to be provided.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus. See MPEP 2163. In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. As such, knowledge of where an antibody binds provides no information as to what such an antibody necessarily looks like (i.e. its primary amino acid structure). Applicant is reminded that the courts have long ruled that “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 University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody (such as the epitope to which a test antibody binds or the fact that it does or does not inhibit some enzymatic process) does not provide evidence of possession of the antibody itself.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. 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 (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., see entire document, particularly the abstract and the middle of the left column of page 1982). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
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), the following is noted. 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). Further, 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). Indeed, the courts have long ruled that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Also, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69. It should also be noted that the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. This Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies and states: “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”. Further, the courts have indicated that the enablement and written description requirements of 35 USC 112 are separable as can be seen in for example Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111.
Artisans concur with such reasoning because they know that knowledge of a given antigen provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al. teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 x 1014).
The instant claimed antibody products do not recite conventional antibodies that have six CDRs as discussed above but are immunoglobulin single variable domains, a class of antibodies derived from camelid heavy chain antibodies (VHH) which are distinct in that they comprise only a single polypeptide chain, and thus only have 3 CDRs which are responsible for antigen binding (see for example pages 31-33 of the instant specification). However, the majority of antigen contacts are still found within the CDRs (Ghahroudi et al., see entire document), and thus it is the structures of the CDRs which give rise to the function of antigen binding. Independent claim 1 recites no specific structure which gives rise to the function of binding MMP, ADAMTS, and/or aggrecan and thus the claim utilizes strictly functional language to characterize the instant claimed products. Other claims, such as claim 4, do recite some level of partial structure. Claim 4 recites SEQ ID numbers for the three CDRs of the ISVD/VHH which binds MMP13 but all of the CDRs are recited as a genus encompassing 1, 2, or 3 mutations as compared to the recited SEQ ID number in addition to the sequence of the SEQ ID number itself. Thus, applicant actively seeks to modify the very structure which the art recognizes as being responsible for the function of antigen binding. The present claim language allows for such mutations/sequence differences to occur anywhere along the recited SEQ ID number and such changes are not in any way constrained as to the type of alteration, such as conservative substitution, non-conservative substitution, addition, deletion, inversion, etc. Thus claim 4 encompasses 3 totally random mutations in each of the three recited CDRs yet the claimed molecules are still required to bind MMP13. Given that mutagenesis data does not appear to be disclosed in the instant specification, and given that even a change as small as a single CDR residue can abrogate binding as evidenced by Rudikoff, it does not appear reasonable that the breadth of structures encompassed by claim 4 for example actually maintain the recited function of binding to MMP13 except for those ISVD which contain the entirety of SEQ ID NOs:8, 10, and 12. Additionally, it should be noted that even if claim 4 was limited to require SEQ ID numbers 8, 10, 12, that amount of structure would not provide insight into the structures of the ISVD which must be present to bind aggrecan and ADAMTS. Similarly, claim 6 which is limited to a fully defined VHH/ISVD for the part that binds MMP13 does not provide any structure concerning the other required binding domains. As has been previously stated, claiming a binding polypeptide by reciting the structure/antigen which is bound rather than providing the structure which gives rise to this functional property (such as by recitation of particular biological sequence or clone name) is typically insufficient to provide adequate written description of that which has been claimed, and claim 6 recites the presence of ISV in the claimed polypeptide complex that bind antigens other than MMP13 which are described only by identifying the antigen to which they bind. Such claim language is of course strictly functional as no particular structure is recited which gives rise to the indicated functional properties. Other dependent claims are essentially equivalent, such as claim 8 and its dependent claims which only specify information for the ADAMTS5 binding and claim 11 and its dependent claims which do the same for aggrecan binding domains. Claim 16 is notable in that it recites SEQ ID NOs:1 and 62, two full length constructs containing one copy of 62C02 (anti-MMP13), one copy of 02F03 (anti-ADAMTS5) and two copies of 114F08 (anti-aggrecan) and differing from one another only in the sequence of the linkers which join together the VHH/ISVD domains in the claimed fusion polypeptides (see also example 4). However, in addition to the exact polypeptides of SEQ ID numbers 1 and 62, claim 16 also recites “at least 95% identical thereto” and as discussed above such language allows for the location of random mutations including into the CDRs which are the structures based upon the evidence presently of record which are required to give rise to the recited functional properties of antigen binding. As discussed above, the art recognizes that changes as small as a single CDR residue can abrogate binding and applicant has not supplied data demonstrating what changes are or are not commensurate with maintenance of antigen binding activity. Therefore, artisans would not readily accept that random sequence alterations as encompassed by the present claim language are reasonably correlated with the function of antigen binding and in the absence of mutagenesis data no reasonable number of species lying with the claimed genus that maintain the requisite functional properties have been disclosed.
Thus, the instant specification discloses a limited number of fusion polypeptides which are correlated with the function of binding aggrecan, MMP13, and ADAMTS5, all of which comprise the 62C02, 02F03, and 114F08 clones, yet the breath of structures encompassed by the instant claims is much broader than the constructs identified in the examples disclosed by applicant. Such broadened subject matter is not reasonably expected to maintain the function of binding the recited antigens for the reasons discussed above. Therefore, in view of the facts that the full length VHH/ISVD constructs disclosed by applicant are not representative of the breadth of structures encompassed by the instant claims and the fact that no correlation between structure and the function of antigen binding appears to be disclosed except for VHH/ISVD which comprise three fully defined CDRs which are known to bind the recited antigen, skilled artisans would reasonably conclude that applicants were not in possession of the full genus of claimed fusion polypeptides and their associated ISVD at the time the instant application was filed.
Claims 1, 3, 4, 6-8, 10, 11, 13, 14, 16, 17, 19, 20, 24, and 26 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant has broadly claimed polypeptides comprising immunoglobulin single variable domain (ISVD) wherein said ISVD bind various antigens including a generic matrix metalloproteinase, a generic ADAMTS, and aggrecan, with dependent claims specifying that the MMP is MMP13 and that the ADAMTS is ADAMTS5 (see particularly claims 1, 3, and 7). Given that the claimed polypeptide comprise ISVD of more than one binding specificity, the most reasonable way to make such reagents is via the techniques of molecular biology, and for dependent claims specifying exact biological sequences defined by SEQ ID number, recombinant antibody production really is the only practical way to make what has been claimed (and indeed is how applicant made such reagents as disclosed in the instant working examples). The instant specification discloses that the anti-MMP13 ISVD named 62C02, the anti-ADAMTS5 ISVD clone named 02F03, and the anti-aggrecan ISVD named 114F08 were obtained following a large amount of screening (see working examples 1-3), with example 4 indicating that 62C02, 02F03, and 114F08 were joined together in various orientations and copy numbers in order to generate fusion polypeptides specific for MMP13, ADAMTS5, and aggrecan, with such constructs being tested for binding activity against human, monkey, and rat antigenic targets in example 5. The synthesized fusion protein are also disclosed as having been tested in in vitro model systems of collagen degradation (examples 6-9) as well as in vivo in rats (examples 10-14). No data appears to be provided concerning mutagenesis, such as CDR affinity maturation data, for clones 62C02, 02F03, and 114F08 in the specification as filed.
As discussed above, the most reasonable way for artisans to make the claimed fusion proteins, particularly ones required to comprise particular sequences or subsequences thereof defined by SEQ ID number is via the tools and techniques of recombinant antibody production. It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. 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 (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., see entire document, particularly the abstract and the middle of the left column of page 1982). The instant claimed antibody products do not recite conventional antibodies that have six CDRs as discussed above but are immunoglobulin single variable domains, a class of antibodies derived from camelid heavy chain antibodies (VHH) which are distinct in that they comprise only a single polypeptide chain, and thus only have 3 CDRs which are responsible for antigen binding (see for example pages 31-33 of the instant specification). However, the majority of antigen contacts are still found within the CDRs (Ghahroudi et al., see entire document), and the CDRs which are critical for the function of antigen binding. Indeed, the criticality of CDRs for antigen binding function is well known in the art as most recombinant antibody production techniques, including humanization, typically require a complete set of CDRs as a staring point for production as evidenced by for example Kypriyanov et al. (see entire document). However, many of the pending claims recite no sequence information at all (such as claim1) or explicitly allow for mutations to the CDRs (such as can be seen in for example claims 4, 8, and 11). Again, no CDR mutagenesis data has been provided and random mutagenesis is unlikely to yield antibodies that maintain antigen binding activity. It is known in the art that many amino acid residues alter secondary structure, such as proline which often forms kinks in secondary structure, while residues like cysteine and methionine can be involved in disulfide bond formation (Stryer, see entire selection). Other residues can introduce either positive or negative charge to disrupt electrostatic interactions, or alter hydrophobicity or steric packing (ibid). Therefore artisans would generally not accept that any one of the standard twenty residues could be readily substituted into a location that is known to be structurally important for generating functional activity (i.e. the CDR itself), given that even a change as small as a single CDR residue can abrogate binding as evidenced by Rudikoff. Thus it does not appear reasonable that the breadth of structures encompassed by the instant claims actually will comprise the recited functional activities of specific antigen binding except for those ISVD which contain fully defined CDR sequences. Further note that given that the claimed polypeptides necessarily require binding activity to multiple antigens, it is insufficient to simply define one binding domain, such as can be seen in instant claim 6 for example, in the absence of sequence information for the other antigen binding domains that are necessarily present.
Therefore, in view of the breadth of the claimed invention, the guidance and direction of the instant speciation, and the teachings of the art, artisans would be unable to make and use the full extent of the claimed fusion polypeptides comprising ISVD domains in the absence of first performing additional, unpredictable trial and error basic science and research.
Claim Rejections - 35 USC § 103
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 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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 7, 14, 16, 17, 19, 20, 24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Burden et al. (US 2012/0095193) in view of Silence (US 9,028,816).
Burden et al. disclose multispecific antibody complexes which bind to ADAMTS5 in addition to other antigens (see entire document, particularly the abstract and claims). Antigens bound in addition to ADAMTS5 include MMP13 as well as aggrecan (see particularly paragraph [0121] as well as claims 12 and 21). These claims differ from the instant claimed invention in that while Burden et al. disclose single domain antibodies/VHH (see for example paragraphs [0047-0049] and [0052]), multispecific binding constructs are not explicitly taught as utilizing these types of antibodies.
Silence disclose that ISVD/VHH offer numerous advantages as compared to convention four-chain antibodies including high stability and easy recovery at high yield (see entire document, particularly column 4), with multivalent forms retaining these properties as well as favorable half-life when one of the specificities is for a serum protein (see particularly column 8). Constructs comprising multiple ISVD/VHH are disclosed as being joined together using various polypeptide linker sequences (see particularly the paragraph spanning columns 9 and 10 as well as Table 30).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time of the instant invention to make a construct comprising ISVD/VHH that bind ADAMTS5, its ligand aggergan and MMP13. This is because multispecific antibodies comprising such binding specificities were already known in the art such as that of Burden et al. and the ordinary artisan would be motivated to use VHH rather than conventional antibodies in such constructs in order to gain the advantages of stability and ease of production that are hallmarks of VHH as taught by Silence. Given the numerous working examples of constructs comprising more than one ISVD/VHH disclosed by Silence, artisan would have a very reasonable expectation of success in making such constructs. Additionally, the generic structure of CDRs interspersed by framework regions as recited in instant claim 19 is found in all ISVD/VHH, no specific biological sequence, such as could be identified via SEQ ID number, is recited in the claim. Thus, all VHH have the structure recited in claim 19 as if it did not it would not be an ISVD/VHH. Additionally, while claims 16 and 17 do recite SEQ ID numbers, such sequences are preceded by “preferably” such that as explained in greater detail earlier in this office action, most reasonably means such “preferable” items are examples of what is encompassed by the scope of the claim rather than actual requirements that must be met, because something which is only “preferred” is not 100% required to be present. Thus, the lack of the polypeptide sequences recited in claims 16 and 17 being disclosed by the cited references does not preclude the finding of such claims obvious as the sequences in question are not actual limitations (i.e. something required) of the claimed invention.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 3, 4, 6-8, 10, 11, 13, 14, 16, 17, 19, 20, 24, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,813,307. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims anticipate that which is presently claimed.
It should be noted that the instant application is a continuation of the application which gave rise to the ‘307 patent, and thus all SEQ ID numbers and their underlying biological sequences are necessarily identical.
The issued claims recite polypeptides minimally comprising three ISVD, one that binds MMP13, one that binds ADAMTS5, and one that binds aggrecan, with dependent claims requiring an additional aggrecan binding domain (see all issued claims, particularly 1 and 6). The ISVD of the issued claims are recited as minimally comprising CDR defined by SEQ ID number and thus anticipate the breadth of the instant claimed generic inventions. The issued claims also recite full length ISVD/VHH sequences defined by SEQ ID number that bind MMP13 (i.e. SEQ ID NO:2, see issued claim 2), ADAMTS5 (i.e. SEQ ID NO:3, see issued claim 3), and aggrecan (i.e. SEQ ID NO:4, see issued claim 4). Full length fusion proteins comprising linker sequences are recited as being SEQ ID NOs:1 and 62 (see issued claims 5 and 7) as are pharmaceutical compositions comprising such multispecific polypeptides (see issued claim 8). Thus, the issued claims anticipate the breadth of what is presently claimed.
Claims 1, 11, 13, 14, 20, 24, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,603,401. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims anticipate that which is presently claimed.
Specifically, the issued claims recite polypeptides comprising ISVD that bind aggergan, with issued SEQ ID NO:117 being 100% identical to instant SEQ ID NO:4 (see all issued claims as well as the enclosed sequence alignment). Such ISVD polypeptides are explicitly disclosed as comprising additional ISDV that bind MMPs and ADAMTS family members, with the caveat that the MMP can’t be MMP13 and the ADAMTS cannot be ADAMTS5 (see particularly issued claims 1, 8, and 13). It should be noted that instant claim 1 places no conditions upon the identity of the MMP or ADAMTS member. Pharmaceutical compositions comprising such ISVD are also claimed (see particularly issued claim 12). Therefore, the issued claims anticipate the breadth of what is presently claimed.
Claims 1, 3, 4, 6, 11, 13, 14, 19, 20, 24 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,129,308. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims anticipate that which is presently claimed.
Specifically, the issued claims recite polypeptides comprising ISVD that bind MMP13 and comprise SEQ ID NO:111, which is a 100% match for instant SEQ ID NO:2 (see enclosed sequence alignment). Notably, such anti-MMP13 ISVD are recited as being joined to ISVD that bind aggrecan, with such ISVD being a 100% match for instant SEQ ID NO:4 (see particularly claims 9, 12, and 15, and the enclosed sequence alignment). While such polypeptides are not recited as being present in pharmaceutical compositions, given the fact that they are recited as being administered as part of therapeutic methods (see issued claims 10 and 11), and given that an ISVD polypeptide cannot reasonably be administered unless it is in a composition, pharmaceutical compositions comprising the products claimed in the ‘308 patent are exceedingly obvious.
Claims 1, 7, 14, 20, 24, and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11, 46, 48, 49, 52-555, 59, 65, 76, 83, 91-95 of copending Application No. 18/145,989. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims anticipate that which is presently claimed.
The copending claims recite polypeptides comprising ISVD that bind aggrecan, as well as additional antigens including MMPs and ADAMTS members with the negative limitation that the MMP bound cannot be MMP13 (see all copending claims, particularly 11 and 91). It should be pointed out that instant claim 1 encompasses ISVD binding to any MMP, and thus excluding MMP13 necessarily decreases the scope of the claimed invention. The use of peptide linkers, as well as the presence of pharmaceutical compositions are all claimed (see particularly copending claims 82, 83, 92, and 93). .
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
It should be noted that the claims of the ‘989 application stand allowed but have not yet issued as a printed patent. Note that when they do issue (the issue fee was paid 8/19/2026) the rejection will cease to be of a provisional nature, and ay reformulation of the rejection necessitated by the patent’s issuance will NOT preclude a finding of finality in the next office action.
No claims are allowable.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1644
Prosecution Insights