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 .
Election/Restrictions
Applicant's election with traverse of species I, drawn to a method of treating or preventing osteoarthritis in a subject comprising administering the recited anti-connexin-43 antibody or fragment thereof, in the reply filed on 05/04/2026 is acknowledged. The traversal is on the ground(s) that there is no undue search burden in examining the subject matter of all claims. This is not found persuasive because search burden is not a factor used in determining whether inventions have a special technical feature that makes a contribution over the prior art in order to establish unity of invention.
The requirement is still deemed proper and is therefore made FINAL.
Claims 2, 3, and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 05/04/2026.
Claim Interpretation
The term “tag sequence” as recited in instant claim 39 does not appear to be specifically defined within the specification. For the purposes of examination, the term “tag sequence” will be interpreted to mean an amino acid or nucleic acid sequence that can be linked to an antibody to facilitate detection of an antigen of interest or purification of the antibody.
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.
Written Description
Claims 1, 25-29, 31-37, and 39-42 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.
Claim 1 encompasses antibody or antigen-binding fragment comprising partially defined VH or VL domains in which at most 10% of the amino acid sequences can vary in the framework and/or CDR domains. Thus claim 1 encompasses antibodies or fragments thereof that have only a single domain and thus less than six CDRs required for a conventional antibody to bind to antigen. Further, the claim encompasses antibodies or fragments thereof having random, undefined amino acid mutations in the VH and VL chains –including in the CDR domains –which can negatively impact antigen binding. All claims dependent directly or indirectly on claim 1 do not cure the deficiencies of claim 1 and are thus also rejected.
Claims 25-26 (which depend on claim 1) further recite that the antibody or fragments thereof comprise heavy chain or light chain CDR variants, respectively. Thus, the antibodies or fragments thereof can have random, undefined amino acid mutations in the CDR domains which, as stated before, can negatively impact antigen binding.
Similarly, claims 27-29 (which depend directly or indirectly from claim 25) further recites that the CDRs of the claimed antibody comprises at least one amino acid substitution or is at least 60% identical to the recited sequences and thus also permits amino acid mutations in the CDR domains that can disrupt antigen binding.
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 (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 at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
Claim 1 recites an antibody or antibody fragment comprising the amino acid sequence of VH chain having at least 90% homology to SEQ ID NO: 58 or the amino acid sequence of a VL chain having at least 90% homology to SEQ ID NO: 60.
It is well-known in the art that, in order to bind antigen, a conventional antibody or antigen- binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6). Because CDRs from both VH and VL domains contribute to the antigen- binding site, it is the combination of both the heavy and the light chain, and not either alone, that determines the final antigen specificity. As presently written, claim 1 recites the VH or VL chains of the anti-connexin-43 antibody M1, which is a conventional antibody (see Pages 20-21 and Tables 1-2 of Specification) and thus requires six CDRs for antigen binding. Thus, artisans would not reasonably expect the structure of only a single domain of the anti-connexin-43 antibody to have the functional property of binding to the target antigen and treating osteoarthritis in a subject.
Further, claim 1 recites partially defined VH and VL chains in which at most 10% of the amino acid sequences can vary. Such variation can occur by amino acid substitution, deletion, or insertion and can be made in the CDRs of the antibodies. However, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the VH and/or VL chains of the antibodies –particularly in the CDR sequences – such that the ability of the antibody to bind to connexin-43 and treat osteoarthritis in a subject is retained. Indeed, it is well-known in the art that amino acid substitutions in the antibody in the CDR domains can negatively impact binding activity (see, e.g. Piche-Nicholas et al, see in particular, Abstract, of record; Colman, see entire document particularly Page 33, Col. 2; and Rudikoff et al, see Abstract) –and conservative amino acid substitutions are no exception. For example, site-directed mutagenesis studies of the NC10 scFv antibody fragment revealed that the tyrosine at position 32 (TyrL32) is a critical residue for binding to influenza virus neuraminidase since mutation of the TyrL32 residue to phenylalanine (a conservative amino acid substitution) resulted in a significant reduction in binding affinity (Dougan et al, see Abstract). Thus, even a single conservative amino acid substitution at a critical residue can significantly reduce or abolish binding to target antigen. Taken together, the effect of amino acid mutations –even conservative substitutions— on antibody binding affinity is not readily predictable. The level of skill and knowledge in the art is such that one of ordinary skill would not be able to readily identify without further testing which amino acid mutations can be made in the VH and VL sequences of the anti-connexin-43-antibody—particularly in the CDR sequences— such that the ability of the antibodies to bind to target antigen and treat osteoarthritis is retained. All claims dependent directly or indirectly from claim 1 do not cure all of the deficiencies of claim 1 and are thus also rejected.
Similarly, claims 25 and 26 recite that VH and VL chain of the antibody or fragment thereof comprises CDR variants. Per the specification, a ‘variant’ can mean a difference in some way relative to the reference sequence other than just a simple deletion of an N- and/or C-terminal amino acid residue or residues. However, as stated above, there is no guidance provided in the specification about which specific amino acids mutations (e.g. substitutions) can be made in each CDR of the VH and VL chains of the antibodies or antibody fragments—such that the ability of the resultant antibody to bind to connexin-43 and inhibit the opening of a Cx43 hemichannel is retained. Claims 27 – 29 (which depend directly or indirectly on claim 25) do not cure the deficiencies of claim 25 and are thus also rejected. In particular, claims 27 and 28 further recite that the CDRs comprise at least one amino acid substitution relative to the parent CDR, wherein the at least one amino acid substitution is the replacement of cysteine or glycine with another amino acid; yet neither the claim nor specification specifies the specific amino acid replacement(s) (including location and number) in the CDRs that can be made such that the resulting antibody retains the functional properties and therapeutic outcomes set forth in the claims. While claim 29 recites that the antibody comprises both VH and VL chains, each CDR is 60% identical to the recited sequences and thus can encompass random, undefined amino acid mutations; but the specification does not provide guidance on identifying which antibodies having these CDR variants possess claimed functional properties.
Therefore, the claimed genus of antibodies lacks adequate written description because there does not appear to be any correlation between the structure of the claimed antibodies or fragments thereof and the function of binding to connexin-43 and treating osteoarthritis in a subject. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of antibodies or fragments thereof that bind to connexin-43 and treating osteoarthritis at the time the instant application was filed.
Scope of Enablement
Claims 1, 25-29, 31-37, and 39-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an anti-connexin-43 antibody or antigen-binding fragment having six fully defined CDRs, does not reasonably provide enablement for antibody variants comprising undefined amino acid mutations in the CDR sequences, wherein the specification provides no data or technical guidance demonstrating that such antibody variants retain the ability to bind to connexin-43 and inhibit the opening of a connexin-43 hemichannel in order to treat osteoarthritis in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The nature of the invention relates to anti-connexin-43 antibodies and fragments thereof and their use in treating or preventing osteoarthritis in a subject (see Background and Summary of the Invention).
Claim 1 is broadly drawn to a method of treating or preventing osteoarthritis in a subject comprising administering to the subject an anti-connexin-43 antibody or fragment thereof , wherein the antibody or fragment thereof comprises either a VH chain or VL chain at least 90% identical to SEQ ID NO: 58 or SEQ ID NO: 60, respectively.
The specification teaches that the anti-connexin 43 (Cx43) hemichannel antibody M1, a murine antibody comprising the VH and VL chains of SEQ ID NOs: 58 and 60 recited in the instant claims, inhibited opening of the Cx43 hemichannel and osteoarthritis progression in a mouse model (see Pages 20-21, Tables 1-2, and Examples 1 and 2). Further disclosed is another murine anti-Cx43 antibody M2 as well as variants of M1 and M2 (see Tables 1 and 2). However, the specification does not provide evidence that random, undefined amino acid mutations made in the VH and VL chains – particularly in the CDRs – of the claimed antibody predictably results in the recited functional properties. Further, the specification lacks sufficient guidance on which amino acid residues, particularly in the CDR sequences, are amenable to mutagenesis without disrupting the ability of the antibody to bind to connexin-43 and inhibit opening of the hemichannel in order to treat osteoarthritis in a subject.
It is well-known in the art that, in order to bind antigen, a conventional antibody or antigen- binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6). Because CDRs from both VH and VL domains contribute to the antigen- binding site, it is the combination of both the heavy and the light chain, and not either alone, that determines the final antigen specificity. The VH and VL chains recited in claim 1 are derived from the anti-Cx43 antibody clone M1, which is a conventional antibody. However, as presently written, the anti-Cx43 antibodies of claim 1 can have a single domain (either VH or VL) and thus less than six CDRs required for antigen-binding. Without further evidence, artisans would not reasonably expect the single domain of the anti-Cx43 antibody M1 to have the functional property of binding to connexin-43 and inhibiting the opening of a Cx43 hemichannel in order to treat or prevent osteoarthritis in a subject.
Further, claim 1 recites partially defined VH and VL chains in which at most 10% of the amino acid sequences can vary. Such variation can occur by amino acid substitution, deletion, or insertion and can be made in the CDRs of the antibodies. However, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the VH and/or VL chains of the antibodies –particularly in the CDR sequences – such that the ability of the antibody to bind to connexin-43 and treat osteoarthritis in a subject is retained. Indeed, amino acid mutations in the CDR domains of an antibody can negatively impact binding activity (see, e.g. Piche-Nicholas et al, see in particular, Abstract, of record; Colman, see entire document particularly Page 33, Col. 2; and Rudikoff et al, see Abstract) –and conservative amino acid substitutions are no exception. For example, site-directed mutagenesis studies of the NC10 scFv antibody fragment revealed that the tyrosine at position 32 (TyrL32) is a critical residue for binding to influenza virus neuraminidase since mutation of the TyrL32 residue to phenylalanine (a conservative amino acid substitution) resulted in a significant reduction in binding affinity (Dougan et al, see Abstract). Thus, even a single conservative amino acid substitution at a critical residue can significantly reduce or abolish binding to target antigen. Accordingly, in the context of antibody-antigen interactions, the effect of amino acid mutations –even conservative substitutions— on binding affinity is not readily predictable. All claims dependent indirectly or directly on claim 1 fail to cure the deficiencies of claim 1 and are thus also rejected.
Claims 25 and 26 further recite that VH and VL chain of the antibody or fragment thereof comprises CDR variants. Per the specification, a ‘variant’ can mean a difference in some way relative to the reference sequence other than just a simple deletion of an N- and/or C-terminal amino acid residue or residues. However, as stated above, there is no guidance provided in the specification about which specific amino acids mutations (e.g. substitutions) can be made in each CDR of the VH and VL chains of the antibodies or antibody fragments—such that the ability of the resultant antibody to bind to connexin-43 and inhibit the opening of a Cx43 hemichannel is retained. Claims 27 – 29 (which depend directly or indirectly on claim 25) do not cure the deficiencies of claim 25 and are thus also rejected. In particular, claims 27 and 28 further recite that the CDRs comprise at least one amino acid substitution relative to the parent CDR, wherein the at least one amino acid substitution is the replacement of cysteine or glycine with another amino acid; yet neither the claim nor specification specifies the specific amino acid replacement(s) (including location and number) in the CDRs that can be made such that the resulting antibody retains the functional properties and therapeutic outcomes set forth in the claims. While claim 29 recites that the antibody comprises both VH and VL chains, each CDR is 60% identical to the recited sequences and thus can encompass random, undefined amino acid mutations; but the specification does not provide guidance on the location, type, and number of amino acid mutations that can be made in the CDRs to yield an antibody with the claimed functional properties.
A person of ordinary skill in the art at the time of filing would have had experience in antibody engineering, including CDR mutagenesis and screening techniques. Even at this high level of skill, however, the effect of randomly mutating amino acids in the CDRs on antigen binding and inhibitory activity cannot be readily predicted without additional testing. In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement (MPEP 2164.06). Thus, the level of skill does not obviate the need for substantial experimentation across the full scope of the claimed genus especially given that there is no guidance provided in the specification or prior art on which amino acid mutations can be made in the CDR domains that will result in a functional variant that still binds to the target antigen connexin-43 and inhibit opening of the connexin hemichannel in order to treat osteoarthritis in a subject.
Therefore, the specification is not enabling over the full scope of the claims.
Claim Rejections - 35 USC § 102
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.
Claims 1, 25-29, 31-36, and 40-42 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Jiang et al (WO2017147561A1), hereinafter Jiang.
Jiang discloses a method of treating or preventing an inflammatory disease in a subject comprising administering to the subject an effective amount of either an antibody that binds connexin 43 (Cx43) hemichannel and inhibits channel opening or a vector encoding said antibody, wherein the inflammatory disease is osteoarthritis (Abstract, Para. 0019, Claims 15, 17 18, 19, and 20). In some embodiments, the anti-Cx43 antibody comprises the VH chain of SEQ ID NO: 58 (corresponding to SEQ ID NO: 58 of the instant claims); and the VL chain of SEQ ID NO: 63 (corresponding to SEQ ID NO: 60 of the instant claims) (Para. 0013). The VH chain comprises the CDRs of SEQ ID NOs: 19, 20, and 21 (corresponding to SEQ ID NOs: 19, 20, and 21 of the instant claims) whereas the VH chain the CDRs of SEQ ID NOs: 31, 32, and 33 (corresponding to SEQ ID NOs: 31, 32, and 33 of the instant claims) (Para. 0013). The antibody can be a humanized antibody, and the antigen-binding fragment thereof can be a Fab, Fab’, or F(ab’)2 fragment (Para. 0038). In some embodiments, the antibody can comprise variant CDR at least 90% identical to a parent CDR (Para. 0077). Substitutions, deletions, insertions or any combination thereof may be used to arrive at a final derivative or variant (Para. 0080). Substitutional variants typically contain the exchange of one amino acid for another at one or more sites within the protein. Conservative substitutions well known in the art include cysteine to serine or glycine to proline (Para. 0097). Further disclosed is a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier (Para. 0032). The pharmaceutical composition may be administered systemically such as intravenously, intradermally, intratumorally, intramuscularly, intraperitoneally, subcutaneously, or locally (Para. 0022). Pharmaceutical compositions of the can also be administered as combination therapy, i.e., combined with other agents (Para. 00108 and Para. 00136). Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. For sterile injectable solutions, the preferred method of preparation is freeze-drying (lyophilization) that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof (Para. 00112-00113). Thus, the pharmaceutical composition comprising the anti-Cx43 antibody can be lyophilized.
Therefore, Jiang meets the limitations of instant claims 1, 25-29, 31-36, and 40-42.
Claim Rejections - 35 USC § 103
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.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Jiang, as applied to claims 1, 25-29, 31-36, and 40-42 above, and further in view of Santos et al (ES2710220A1), hereinafter Santos.
The teachings of Jiang have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody is administered in combination with one of the secondary therapeutic agents recited in claim 37.
However, Santos discloses a method for treating or preventing osteoarthritis in a subject comprising administering a therapeutically effective amount of an anti-connexin compound that inhibits the opening of a connexin hemichannel (Abstract, Para. 0008, Para. 0030, Para. 0083, Para. 0085, Para. 0099, and Para. 0112), wherein the anti-connexin compound is an anti-Cx43 antibody or antigen-binding fragment and (Para. 0042 and Para. 0070). The anti-connexin-43 antibody can be administered in combination with a second active agent selected from non-steroidal anti-inflammatory drugs (NSAIDS), glucosamine and chondroitin, cyclooxygenase-2 inhibitors, tramadol, opiates, capsaicin, topical salicylate, intraarticular steroids, and intra-articular hyaluronic acid (Para. 0095 and Para. 0097).
It would have been obvious to one of ordinary skill in the art to administer the anti-Cx43 antibody of Jiang in combination with a secondary active agent such as an NSAID, glucosamine, and/or chondroitin. One of ordinary skill in the art would have been motivated to do so since the combination of an anti-connexin compound (e.g. anti-connexin-43) and an NSAID, glucosamine, and/or chondroitin can be used to treat osteoarthritis in a subject as taught by Santos. Therefore, one of ordinary skill in the art would reasonably expect that the anti-Cx43 antibody of Jiang administered in combination with an NSAID, glucosamine, and/or chondroitin can effectively treat osteoarthritis in a subject.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Jiang, as applied to claims 1, 25-29, 31-36, and 40-42 above, and further in view of Berg et al (Berg, Eric A, and Jordan B Fishman. “Labeling Antibodies.” Cold Spring Harbor protocols vol. 2020,7 099242. 1 Jul. 2020, doi:10.1101/pdb.top099242), hereinafter Berg.
The teachings of Jiang have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody comprises a “tag sequence”.
However, Berg teaches that labeling of antibodies facilitates the detection of antigen(s) of interest in a cell or tissue section (see Introduction). Examples of labels that can be used include biotin, whose small size (244 Da) generally has little effect on the biological activity of the protein target. Streptavidin and avidin – biotin’s binding partners – can also be labeled with a dye or detection reagent and the used in concert with a biotinylated antibody to increase the reagent’s versatility and amplify the output signal (see “Labeling Antibodies by Biotinylation” section on Page 256). Without further limitation, a “tag sequence” as recited in instant claim 39 can encompass detectable labels.
It would have been obvious to one of ordinary skill in the art to modify the anti-Cx43 antibody such that it comprises a detectable label (or ‘tag sequence’) such as biotin. One of ordinary skill in the art would have been motivated to do so since labelling antibodies such as with biotin allows for the detection of antigens of interest in a biological sample as taught by Berg. Therefore, one of ordinary skill in the art would reasonably expect the anti-Cx43 antibody comprising a detectable label/tag sequence such as biotin can be used to effectively visualize antigens of interest (in this case, Cx43 hemichannels) in a biological sample.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1, 25, 26, 29, 32-34, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9914775B2.
The issued claims recite a method of treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject an effective amount of an antibody or antigen-binding portion thereof that binds to a connexin 43 (Cx43) hemichannel (issued claim 1), wherein the inflammatory disorder is osteoarthritis (issued claim 3). The antibody or antigen-binding portion thereof is administered intravenously, intramuscularly, subcutaneously, or parenterally (issued claim 9). The antibody or antigen-binding portion thereof comprises the ‘heavy chain’ of SEQ ID NO: 6 and the ‘light chain’ of SEQ ID NO: 8 (issued claims 1 and 13) (Note: the amino acid sequences of SEQ ID NOs: 6 and 8 appears to be variable regions only). The ‘heavy chain’ of SEQ ID NO: 6 is 92.6% identical to SEQ ID NO: 58 of the instant claims, having a single amino acid mutation in the framework region and thus fully comprising the CDRs of SEQ ID NOs: 19, 20, and 21. The ‘light chain’ of SEQ ID NO: 8 is 92.6% identical to SEQ ID NO: 60 of the instant claims, having a single amino acid mutation in the framework region and thus fully comprising the CDRs of SEQ ID NOs: 31, 32, and 33 (see Sequence Alignment-340 vs. 511 on OA.Appendix as well as Pages 20-21 and Tables 1 and 2 of instant specification) (note: the sequence alignment results use sequences pulled from application 18/583,340, which is in the same patent family). In order to be suitable for therapeutic use, the anti-Cx43 antibody is necessarily administered in a pharmaceutically acceptable formulation.
Thus, the issued claims meet the limitations of instant claims 1, 25, 26, 29, 32-34, and 40.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9914775B2, as applied to claims 1, 25, 26, 29, 32-34, and 40 above, in view of Almargo et al (Almagro, Juan C, and Johan Fransson. Frontiers in bioscience : a journal and virtual library vol. 13 1619-33. 1 Jan. 2008), hereinafter Almargo.
The teachings of the issued claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody is humanized.
However, Almargo teaches that antibody humanization is designed to produce a molecule with minimal immunogenicity when applied to humans, while retaining the specificity and affinity of the parental non-human antibody (see entire document, in particular, Abstract and Introduction).
It would have been obvious to one of ordinary skill in the art to humanize the anti-Cx43 antibody of the issued claims for use in treating osteoarthritis in a subject. One of ordinary skill in the art would have been motivated to so since humanized antibodies have minimal immunogenicity when applied to humans, while retaining the specificity and affinity of the parental non-human antibody as taught by Almargo. Therefore, one of ordinary skill in the art would reasonably expect that a humanized anti-Cx43 antibody to be safer and more effective in treating osteoarthritis in a subject, particularly human subjects.
Claims 36 and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9914775B2, as applied to claims 1, 25, 26, 29, 32-34, and 40 above, in view of Santos et al (ES2710220A1), hereinafter Santos.
The teachings of issued claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody is administered in combination with one of the secondary therapeutic agents recited in claim 37.
However, Santos discloses a method for treating or preventing osteoarthritis in a subject comprising administering a therapeutically effective amount of an anti-connexin compound that inhibits the opening of a connexin hemichannel (Abstract, Para. 0008, Para. 0030, Para. 0083, Para. 0085, Para. 0099, and Para. 0112), wherein the anti-connexin compound is an anti-Cx43 antibody or antigen-binding fragment and (Para. 0042 and Para. 0070). The anti-connexin-43 antibody can be administered in combination with a second active agent selected from non-steroidal anti-inflammatory drugs (NSAIDS), glucosamine and chondroitin, cyclooxygenase-2 inhibitors, tramadol, opiates, capsaicin, topical salicylate, intraarticular steroids, and intra-articular hyaluronic acid (Para. 0095 and Para. 0097).
It would have been obvious to one of ordinary skill in the art to administer the anti-Cx43 antibody of the issued claims in combination with a secondary active agent such as an NSAID, glucosamine, and/or chondroitin. One of ordinary skill in the art would have been motivated to do so since the combination of an anti-connexin compound (e.g. anti-connexin-43) and an NSAID, glucosamine, and/or chondroitin can be used to treat osteoarthritis in a subject as taught by Santos. Therefore, one of ordinary skill in the art would reasonably expect that the anti-Cx43 antibody of the issued claims administered in combination with an NSAID, glucosamine, and/or chondroitin can effectively treat osteoarthritis in a subject.
Claim 39 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9914775B2, as applied to claims 1, 25, 26, 29, 32-34, and 40 above, in view of Berg et al (Berg, Eric A, and Jordan B Fishman. “Labeling Antibodies.” Cold Spring Harbor protocols vol. 2020,7 099242. 1 Jul. 2020, doi:10.1101/pdb.top099242), hereinafter Berg
The teachings of the issued claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody comprises a “tag sequence”.
However, Berg teaches that labeling of antibodies facilitates the detection of antigen(s) of interest in a cell or tissue section (see Introduction). Examples of labels that can be used include biotin, whose small size (244 Da) generally has little effect on the biological activity of the protein target. Streptavidin and avidin – biotin’s binding partners – can also be labeled with a dye or detection reagent and the used in concert with a biotinylated antibody to increase the reagent’s versatility and amplify the output signal (see “Labeling Antibodies by Biotinylation” section on Page 256). Without further limitation, a “tag sequence” as recited in instant claim 39 can encompass detectable labels.
It would have been obvious to one of ordinary skill in the art to modify the anti-Cx43 antibody of the issued claims such that it comprises a detectable label (or ‘tag sequence’) such as biotin. One of ordinary skill in the art would have been motivated to do so since labelling antibodies such as with biotin allows for the detection of antigens of interest in a biological sample as taught by Berg. Therefore, one of ordinary skill in the art would reasonably expect the anti-Cx43 antibody of the issued claims comprising a detectable label/tag sequence such as biotin can be used to effectively visualize antigens of interest (in this case, Cx43 hemichannels) in a biological sample.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9914775B2, as applied to claims 1, 25, 26, 29, 32-34, and 40 above, in view of Holliger et al (Holliger, Philipp, and Peter J. Hudson. Nature biotechnology 23.9 (2005): 1126-1136), hereinafter Holliger.
The teachings of the issued claims have been discussed above and differ from the instantly claimed invention in it is not specifically taught the anti-Cx43 antigen binding fragment is, for example, a Fab fragment.
However, Holliger teaches that antibody Fab fragments, comprising both VH and VL domains, retain the specific, monovalent, antigen-binding affinity of the parent IgG, while showing improved pharmacokinetics for tissue penetration due to their small size. Further, elimination of the Fc domain can remove undesired Fc-mediated effects such as long half-life and activation of cytokine release (see Abstract, third paragraph of “Natural and synthetic fragment design” section, and “Fab, Fv and single V-type domains” section).
It would have been obvious to one of ordinary skill in the art to modify the anti-Cx43 antibody fragment of the issued claims such that it is, for example, a Fab fragment. One of ordinary skill in the art would have been motivated to do so since Fab fragments retain the specific, monovalent, antigen-binding affinity of the parent IgG, while showing improved pharmacokinetics for tissue penetration due to their small size as taught by Holliger. Therefore, one of ordinary skill in the art would reasonably expect that an anti-Cx43-antibody fragment that is a Fab v fragment would have improved efficacy in the treatment of osteoarthritis in a subject.
Claims 1, 25, 26, 29, 31-36, 40, 41, and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10633442B2 in view of Jiang et al (WO2017147561A1), hereinafter Jiang.
The issued claims recite an antibody or antigen-binding portion thereof that comprises the heavy and light chain CDRs of SEQ ID NOs: 6 and 8, respectively (note: the amino acid sequences of SEQ ID NOs: 6 and 8 appears to be variable regions only), wherein the antibody binds to a Cx43 hemichannel and inhibits the opening of a Cx43 hemichannel (issued claims 5 and 6). The ‘heavy chain’ of SEQ ID NO: 6 is 92.6% identical to SEQ ID NO: 58 of the instant claims, having a single amino acid mutation in the framework region and thus fully comprising the CDRs of SEQ ID NOs: 19, 20, and 21. The ‘light chain’ of SEQ ID NO: 8 is 92.6% identical to SEQ ID NO: 60 of the instant claims, having a single amino acid mutation in the framework region and thus fully comprising the CDRs of SEQ ID NOs: 31, 32, and 33 (see Sequence Alignment-340 vs 511 on OA.Appendix as well as Pages 20-21 and Tables 1 and 2 of instant specification) (note: the sequence alignment results use sequences pulled from application 18/583,340, which is in the same patent family). The antigen-binding portion can be a Fab fragment, a Fab′ fragment, or a F(ab′)2 fragment (issued claim 9). Further recited is a pharmaceutical composition comprising the anti-Cx43 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier, wherein the composition is lyophilized (issued claims 11 and 12).
The issued claims do not recite a method of treating or preventing osteoarthritis in a subject comprising administering an anti-Cx43 antibody to the subject. Further the claims do not recite that the anti-Cx43 antibody is humanized or disposed in an expression vector. Lastly, the claims do not recite that the anti-Cx43 antibody is administered in combination with a second therapeutic agent.
However, Jiang teaches that connexin hemichannels play a role in the pathogenesis of osteoarthritis (see Description of Related Art, Para. 0003-0006) and discloses a method of treating or preventing osteoarthritis in a subject comprising administering to the subject an effective amount of either an antibody that binds connexin 43 (Cx43) hemichannel and inhibits channel opening or a vector encoding said antibody (Abstract, Para. 0019, Claims 15, 17 18, 19, and 20). In some embodiments, the antibody can be a humanized, wherein the rodent amino acid sequences are replaced with corresponding sequences found in human antibodies in order to reduce the likelihood of adverse immune reactions during therapeutic use [in humans] (Para. 0038 and 0093). It is further taught that pharmaceutical compositions comprising an anti-connexin antibody can also be administered as combination therapy, i.e., combined with other active agents (Para. 00108 and Para. 00136).
It would have been obvious to one of ordinary skill in the art to use the anti-Cx43 antibody of the issued claims (or a vector encoding said antibody) in the methods of treating or preventing osteoarthritis in a subject disclosed by Jiang. One or ordinary skill in the art would have been motivated to do so since connexins play a role in the pathogenesis of osteoarthritis; thus, administration of an anti-Cx43 antibody, or a vector encoding said antibody, that binds to and inhibits opening of a Cx43 hemichannel can treat osteoarthritis in a subject as taught by Jiang. Further in view of the teachings of Jiang, artisans would have been motivated to humanize the anti-Cx43 antibody in order to reduce the likelihood of adverse immune reactions during therapeutic use [in humans]. Lastly, artisans would have been motivated to administer the anti-Cx43 antibody in combination with a second active agent since Jiang teaches that combination therapy can be useful in the methods disclosed therein. Therefore, one of ordinary skill in the art would have been motivated to administer a humanized anti-Cx43 antibody of the issued claims, or a vector encoding said antibody, either alone or in combination with a second active agent in order to treat osteoarthritis in a human subject.
Claim 37 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10633442B2 in view of Jiang, as applied to claims 1, 25, 26, 29, 31-36, 40, 41, and 42 above, in view of Santos et al (ES2710220A1), hereinafter Santos.
The teachings of issued claims in view of Jiang have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody is administered in combination with one of the secondary therapeutic agents recited in claim 37.
However, Santos discloses a method for treating or preventing osteoarthritis in a subject comprising administering a therapeutically effective amount of an anti-connexin compound that inhibits the opening of a connexin hemichannel (Abstract, Para. 0008, Para. 0030, Para. 0083, Para. 0085, Para. 0099, and Para. 0112), wherein the anti-connexin compound is an anti-Cx43 antibody or antigen-binding fragment and (Para. 0042 and Para. 0070). The anti-connexin-43 antibody can be administered in combination with a second active agent selected from non-steroidal anti-inflammatory drugs (NSAIDS), glucosamine and chondroitin, cyclooxygenase-2 inhibitors, tramadol, opiates, capsaicin, topical salicylate, intraarticular steroids, and intra-articular hyaluronic acid (Para. 0095 and Para. 0097).
It would have been obvious to one of ordinary skill in the art to administer the anti-Cx43 antibody of the issued claims in combination with a secondary active agent such as an NSAID, glucosamine, and/or chondroitin. One of ordinary skill in the art would have been motivated to do so since the combination of an anti-connexin compound (e.g. anti-connexin-43) and an NSAID, glucosamine, and/or chondroitin can be used to treat osteoarthritis in a subject as taught by Santos. Therefore, one of ordinary skill in the art would reasonably expect that the anti-Cx43 antibody of the issued claims administered in combination with an NSAID, glucosamine, and/or chondroitin can effectively treat osteoarthritis in a subject.
Claim 39 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10633442B2 in view of Jiang, as applied to claims 1, 25, 26, 29, 31-36, 40, 41, and 42 above, and further in view of Berg et al (Berg, Eric A, and Jordan B Fishman. “Labeling Antibodies.” Cold Spring Harbor protocols vol. 2020,7 099242. 1 Jul. 2020, doi:10.1101/pdb.top099242), hereinafter Berg
The teachings of the issued claims in view of Jiang have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody comprises a “tag sequence”.
However, Berg teaches that labeling of antibodies facilitates the detection of antigen(s) of interest in a cell or tissue section (see Introduction). Examples of labels that can be used include biotin, whose small size (244 Da) generally has little effect on the biological activity of the protein target. Streptavidin and avidin – biotin’s binding partners – can also be labeled with a dye or detection reagent and the used in concert with a biotinylated antibody to increase the reagent’s versatility and amplify the output signal (see “Labeling Antibodies by Biotinylation” section on Page 256). Without further limitation, a “tag sequence” as recited in instant claim 39 can encompass detectable labels.
It would have been obvious to one of ordinary skill in the art to modify the anti-Cx43 antibody of the issued claims in view of Jiang such that it comprises a detectable label (or ‘tag sequence’) such as biotin. One of ordinary skill in the art would have been motivated to do so since labelling antibodies such as with biotin allows for the detection of antigens of interest in a biological sample as taught by Berg. Therefore, one of ordinary skill in the art would reasonably expect the anti-Cx43 antibody of the issued claims in view of Jiang comprising a detectable label/tag sequence such as biotin can be used to effectively visualize antigens of interest (in this case, Cx43 hemichannels) in a biological sample.
Claims 1, 25, 26, 29, 31-36, 40, 41, and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11912762B2 in view of Jiang et al (WO2017147561A1), hereinafter Jiang.
The issued claims recite a method of treating osteoarthritis in a subject, the method comprising: administering to the subject an effective amount of an anti-connexin 43 antibody or antigen-binding portion thereof (issued claim 1). The antibody or antigen-binding portion thereof to a connexin 43 (Cx43) hemichannel and inhibits the opening of the Cx43 hemichannel (issued claim 4). The antibody or antigen-binding portion thereof can be administered intravenously, intramuscularly, subcutaneously, or parenterally (issued claim 6). The antigen-binding portion can be a Fab fragment, a Fab′ fragment, or a F(ab′)2 fragment (issued claim 12). In order to be suitable for therapeutic use, the anti-Cx43 antibody is necessarily administered in a pharmaceutically acceptable formulation.
The issued claims do not recite that the anti-connexin-43 antibody or fragment thereof has the VH/VL and CDR sequences recited in the instant claims, wherein the antibody or fragment thereof is humanized. Further, the issued claims do not recite that a pharmaceutical formulation comprising the anti-Cx43 antibody is administered in combination with a second active agent or is lyophilized. Lastly, the issued claims do not recite that the anti-Cx43 antibody or fragment thereof is encoded by an expression vector.
However, Jiang discloses an anti-Cx43 antibody that can be used for treating or preventing osteoarthritis in a subject, wherein the antibody comprises the VH chain of SEQ ID NO: 58 (corresponding to SEQ ID NO: 58 of the instant claims); and the VL chain of SEQ ID NO: 60 (corresponding to SEQ ID NO: 60 of the instant claims) (Para. 0013). The VH chain comprises the CDRs of SEQ ID NOs: 19, 20, and 21 (corresponding to SEQ ID NOs: 19, 20, and 21 of the instant claims) whereas the VH chain the CDRs of SEQ ID NOs: 31, 32, and 33 (corresponding to SEQ ID NOs: 31, 32, and 33 of the instant claims) (Para. 0013, Abstract, Para. 0019, Claims 15, 17 18, 19, and 20). In some embodiments, the antibody can be a humanized antibody, wherein the rodent amino acid sequences are replaced with corresponding sequences found in human antibodies in order to reduce the likelihood of adverse immune reactions during therapeutic use [in humans] (Para. 0038 and 0093). Pharmaceutical compositions comprising an anti-connexin antibody can also be administered as combination therapy, i.e., combined with other active agents (Para. 00108 and Para. 00136). It is further taught that therapeutic compositions comprising the antibody typically must be sterile and stable under the conditions of manufacture and storage. For sterile injectable solutions, the preferred method of preparation is freeze-drying (lyophilization) that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof (Para. 00112-00113). Thus, the pharmaceutical composition comprising the anti-Cx43 antibody can be lyophilized.
It would have been obvious to one of ordinary skill in the art to substitute the antibody of the issued claims with the anti-Cx43 antibody (or a vector encoding said antibody) disclosed by Jiang in the method of treating osteoarthritis in a subject. One of ordinary skill in the art would have been motivated to do so since they have the same function and can be used for the same purpose (i.e. inhibiting the opening of a Cx43 hemichannel and treating osteoarthritis in a subject). An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Further, artisans would have been motivated to humanize the anti-Cx43 antibody in order to reduce the likelihood of adverse immune reactions during therapeutic use [in humans] as taught by Jiang. Additionally, artisans would have been motivated to administer the anti-Cx43 antibody in combination with a second active agent since Jiang teaches that combination therapy can be useful in the methods disclosed therein. Lastly, artisans would have been motivated to modify a pharmaceutical formulation comprising the anti-Cx43 antibody such that it is lyophilized since lyophilization yields antibody-containing compositions that remain sterile and stable during manufacture and storage as taught by Jiang. Therefore, one of ordinary skill in the art would have been motivated to administer a humanized anti-Cx43 antibody of the issued claims, or a vector encoding said antibody, either alone or in combination with a second active agent in order to treat osteoarthritis in a human subject. Moreover, artisans would reasonably expect for a lyophilized pharmaceutical composition comprising the anti-Cx43 antibody of the issued claims to be more sterile and stable during storage and manufacturing.
Claim 37 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11912762B2 in view of Jiang, as applied to claims 1, 25, 26, 29, 31-36, 40, 41, and 42 above, and further in view of Santos et al (ES2710220A1), hereinafter Santos.
The teachings of issued claims in view of Jiang have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody is administered in combination with one of the secondary therapeutic agents recited in claim 37.
However, Santos discloses a method for treating or preventing osteoarthritis in a subject comprising administering a therapeutically effective amount of an anti-connexin compound that inhibits the opening of a connexin hemichannel (Abstract, Para. 0008, Para. 0030, Para. 0083, Para. 0085, Para. 0099, and Para. 0112), wherein the anti-connexin compound is an anti-Cx43 antibody or antigen-binding fragment and (Para. 0042 and Para. 0070). The anti-connexin-43 antibody can be administered in combination with a second active agent selected from non-steroidal anti-inflammatory drugs (NSAIDS), glucosamine and chondroitin, cyclooxygenase-2 inhibitors, tramadol, opiates, capsaicin, topical salicylate, intraarticular steroids, and intra-articular hyaluronic acid (Para. 0095 and Para. 0097).
It would have been obvious to one of ordinary skill in the art to administer the anti-Cx43 antibody of the issued claims in combination with a secondary active agent such as an NSAID, glucosamine, and/or chondroitin. One of ordinary skill in the art would have been motivated to do so since the combination of an anti-connexin compound (e.g. anti-connexin-43) and an NSAID, glucosamine, and/or chondroitin can be used to treat osteoarthritis in a subject as taught by Santos. Therefore, one of ordinary skill in the art would reasonably expect that the anti-Cx43 antibody of the issued claims administered in combination with an NSAID, glucosamine, and/or chondroitin can effectively treat osteoarthritis in a subject.
Claim 39 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11912762B2 in view of Jiang, as applied to claims 1, 25, 26, 29, 31-36, 40, 41, and 42 above, and further in view of Berg et al (Berg, Eric A, and Jordan B Fishman. “Labeling Antibodies.” Cold Spring Harbor protocols vol. 2020,7 099242. 1 Jul. 2020, doi:10.1101/pdb.top099242), hereinafter Berg
The teachings of the issued claims in view of Jiang have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody comprises a “tag sequence”.
However, Berg teaches that labeling of antibodies facilitates the detection of antigen(s) of interest in a cell or tissue section (see Introduction). Examples of labels that can be used include biotin, whose small size (244 Da) generally has little effect on the biological activity of the protein target. Streptavidin and avidin – biotin’s binding partners – can also be labeled with a dye or detection reagent and the used in concert with a biotinylated antibody to increase the reagent’s versatility and amplify the output signal (see “Labeling Antibodies by Biotinylation” section on Page 256). Without further limitation, a “tag sequence” as recited in instant claim 39 can encompass detectable labels.
It would have been obvious to one of ordinary skill in the art to modify the anti-Cx43 antibody of the issued claims in view of Jiang such that it comprises a detectable label (or ‘tag sequence’) such as biotin. One of ordinary skill in the art would have been motivated to do so since labelling antibodies such as with biotin allows for the detection of antigens of interest in a biological sample as taught by Berg. Therefore, one of ordinary skill in the art would reasonably expect the anti-Cx43 antibody of the issued claims in view of Jiang comprising a detectable label/tag sequence such as biotin can be used to effectively visualize antigens of interest (in this case, Cx43 hemichannels) in a biological sample.
Claims 1, 25, 26, 29, 31-36, and 39-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12162937B2 in view of Jiang et al (WO2017147561A1), hereinafter Jiang.
The issued claims recite a method of treating inflammatory disorder in a subject, the method comprising: administering to the subject an effective amount of an anti-connexin 43 antibody or antigen-binding portion thereof (issued claim 1), wherein the inflammatory disorder is osteoarthritis (issued claim 2). The antibody or antigen binding fragment thereof is administered intravenously, intramuscularly, subcutaneously, or parentally (issued claim 8). The antigen-binding portion can be a Fab fragment, a Fab′ fragment, or a F(ab′)2 fragment (issued claim 11).The antibody or antigen-binding fragment can be linked to a detectable label (issued claim 10). Without further limitation, a ‘tag sequence’ per instant claim 39 is interpreted as encompassing detectable labels. In order to be suitable for therapeutic use, the anti-Cx43 antibody is necessarily administered in a pharmaceutically acceptable formulation.
The issued claims do not recite that the anti-connexin-43 antibody or fragment thereof has the VH/VL and CDR sequences recited in the instant claims, wherein the antibody or fragment thereof is humanized. Further, the issued claims do not recite that a pharmaceutical formulation comprising the anti-Cx43 antibody is administered in combination with a second active agent or is lyophilized. Lastly, the issued claims do not recite that the anti-Cx43 antibody or fragment thereof is encoded by an expression vector.
However, Jiang discloses a method of treating or preventing osteoarthritis in a subject comprising administering to the subject an effective amount of either an antibody that binds connexin 43 (Cx43) hemichannel and inhibits channel opening or a vector encoding said antibody (Abstract, Para. 0019, Claims 15, 17 18, 19, and 20). In some embodiments, the anti-Cx43 antibody comprises the VH chain of SEQ ID NO: 58 (corresponding to SEQ ID NO: 58 of the instant claims); and the VL chain of SEQ ID NO: 60 (corresponding to SEQ ID NO: 60 of the instant claims) (Para. 0013). The VH chain comprises the CDRs of SEQ ID NOs: 19, 20, and 21 (corresponding to SEQ ID NOs: 19, 20, and 21 of the instant claims) whereas the VH chain the CDRs of SEQ ID NOs: 31, 32, and 33 (corresponding to SEQ ID NOs: 31, 32, and 33 of the instant claims) (Para. 0013). In some embodiments, the antibody can comprise variant CDR at least 90% identical to a parent CDR (Para. 0077). Further disclosed is a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier (Para. 0032). Pharmaceutical compositions can also be administered as combination therapy, i.e., combined with other active agents (Para. 00108 and Para. 00136). Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. For sterile injectable solutions, the preferred method of preparation is freeze-drying (lyophilization) that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof (Para. 00112-00113). Thus, the pharmaceutical composition comprising the anti-Cx43 antibody can be lyophilized.
It would have been obvious to one of ordinary skill in the art to substitute the antibody of the issued claims with the anti-Cx43 antibody (or a vector encoding said antibody) disclosed by Jiang in the method of treating osteoarthritis in a subject. One of ordinary skill in the art would have been motivated to do so since they have the same function and can be used for the same purpose (i.e. inhibiting the opening of a Cx43 hemichannel and treating osteoarthritis in a subject). An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Further, artisans would have been motivated to humanize the anti-Cx43 antibody in order to reduce the likelihood of adverse immune reactions during therapeutic use [in humans] as taught by Jiang. Additionally, artisans would have been motivated to administer the anti-Cx43 antibody in combination with a second active agent since Jiang teaches that combination therapy can be useful in the methods disclosed therein. Lastly, artisans would have been motivated to modify a pharmaceutical formulation comprising the anti-Cx43 antibody such that it is lyophilized since lyophilization yields antibody-containing compositions that remain sterile and stable during manufacture and storage as taught by Jiang. Therefore, one of ordinary skill in the art would have been motivated to administer a humanized anti-Cx43 antibody of the issued claims, or a vector encoding said antibody, either alone or in combination with a second active agent in order to treat osteoarthritis in a human subject. Moreover, artisans would reasonably expect for a lyophilized pharmaceutical composition comprising the anti-Cx43 antibody of the issued claims to be more sterile and stable during storage and manufacturing.
Claim 37 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12162937B2 in view of Jiang, as applied to claims 1, 25, 26, 29, 31-36, and 39-42 above, and further in view of Santos et al (ES2710220A1), hereinafter Santos.
The teachings of issued claims in view of Jiang have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody is administered in combination with one of the secondary therapeutic agents recited in claim 37.
However, Santos discloses a method for treating or preventing osteoarthritis in a subject comprising administering a therapeutically effective amount of an anti-connexin compound that inhibits the opening of a connexin hemichannel (Abstract, Para. 0008, Para. 0030, Para. 0083, Para. 0085, Para. 0099, and Para. 0112), wherein the anti-connexin compound is an anti-Cx43 antibody or antigen-binding fragment and (Para. 0042 and Para. 0070). The anti-connexin-43 antibody can be administered in combination with a second active agent selected from non-steroidal anti-inflammatory drugs (NSAIDS), glucosamine and chondroitin, cyclooxygenase-2 inhibitors, tramadol, opiates, capsaicin, topical salicylate, intraarticular steroids, and intra-articular hyaluronic acid (Para. 0095 and Para. 0097).
It would have been obvious to one of ordinary skill in the art to administer the anti-Cx43 antibody of the issued claims in combination with a secondary active agent such as an NSAID, glucosamine, and/or chondroitin. One of ordinary skill in the art would have been motivated to do so since the combination of an anti-connexin compound (e.g. anti-connexin-43) and an NSAID, glucosamine, and/or chondroitin can be used to treat osteoarthritis in a subject as taught by Santos. Therefore, one of ordinary skill in the art would reasonably expect that the anti-Cx43 antibody of the issued claims administered in combination with an NSAID, glucosamine, and/or chondroitin can effectively treat osteoarthritis in a subject.
Claim 39 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12162937B2 in view of Jiang, as applied to claims 1, 25, 26, 29, 31-36, and 39-42 above, and further in view of Berg et al (Berg, Eric A, and Jordan B Fishman. “Labeling Antibodies.” Cold Spring Harbor protocols vol. 2020,7 099242. 1 Jul. 2020, doi:10.1101/pdb.top099242), hereinafter Berg
The teachings of the issued claims in view of Jiang have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-Cx43 antibody comprises a “tag sequence”.
However, Berg teaches that labeling of antibodies facilitates the detection of antigen(s) of interest in a cell or tissue section (see Introduction). Examples of labels that can be used include biotin, whose small size (244 Da) generally has little effect on the biological activity of the protein target. Streptavidin and avidin – biotin’s binding partners – can also be labeled with a dye or detection reagent and the used in concert with a biotinylated antibody to increase the reagent’s versatility and amplify the output signal (see “Labeling Antibodies by Biotinylation” section on Page 256). Without further limitation, a “tag sequence” as recited in instant claim 39 can encompass detectable labels.
It would have been obvious to one of ordinary skill in the art to modify the anti-Cx43 antibody of the issued claims in view of Jiang such that it comprises a detectable label (or ‘tag sequence’) such as biotin. One of ordinary skill in the art would have been motivated to do so since labelling antibodies such as with biotin allows for the detection of antigens of interest in a biological sample as taught by Berg. Therefore, one of ordinary skill in the art would reasonably expect the anti-Cx43 antibody of the issued claims in view of Jiang comprising a detectable label/tag sequence such as biotin can be used to effectively visualize antigens of interest (in this case, Cx43 hemichannels) in a biological sample.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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