DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
The claims filed 10/27/2023 have been entered. Claims 1-21 are pending and under
examination.
Priority
The application is a 371 application, filed 10/27/2023, of PCT application
PCT/IB2022/054001, filed 04/29/2022, which claims priority benefits from Provisional No. 63362372, filed 04/01/2022, and Provisional No. 63182561, filed 04/30/2021. The effective filing date of this application is 04/30/2021, the filing date of the provisional application Provisional No. 63182561.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/12/2023, 03/27/2024, and 05/01/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 16-21 objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, claims 16-21 have not been further treated on the merits.
Claim 4 is objected to because of the following informalities: “wherein wherein” appears to be a duplication of wherein.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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
Claim 2 is 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 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.” The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The claim is broadly drawn to a method of treating osteoarthritis comprising of administering to a human subject an ADAMTS5 inhibiting polypeptide comprising at least one immunoglobulin single variable domain (ISVD), comprising of 3 CDRs, wherein the CDR1, 2, and 3 are chosen from the list of SEQ ID NO’s in the claims. However, this limitation does not specify the exact combination of sequences for CDR1, 2, and 3 that make up the ISVD. The broadest reasonable interpretation of the limitation is that the ISVD may comprise any combination of the CDR1, 2, and 3 sequences listed. There are 16, 19, and 19 potential sequences listed for CDR1, CDR2, and CDR3, respectively, so there are 16 x 19 x 19 = 5776 possible ISVD claimed. Thus, the claims encompass a genus of ISVD binding ADAMTS5, each with distinct combinations of CDR1-3 sequences.
The specification teaches only 18 exact combinations of these claimed CDR 1-3 sequences, which are described in the first 18 sequences in Table 3.
Written description is met for these ISVD comprising of the disclosed combinations of CDR 1-3.
However, the invention lacks written description for the entire scope of the claim, specifically for combinations of CDR1-3 not instantly disclosed. The specification is silent on the correlation between structure and function for genus of the ISVDs, specifically, the other claimed species of antibody without instantly disclosed combinations of CDR1-3. In other words, the specification is silent on whether any combination of the claimed CDR1-3 will yield an ISVD that inhibits ADAMTS5 as claimed. Therefore, the specification, providing, only the disclosed combinations of CDR1-3 provides insufficient written description to support the entire scope of the genus of ISVD claimed.
The state of the art teaches that even individual CDRs that are known to exist in antigen-binding polypeptides, produce a high degree of functional variation when combined together in combinations unknown in the art or nature (Soderlind et al, Recombining germline-derived CDR sequences for creating diverse single-framework antibody libraries, Nature Biotech, 18, 852-856 (2000), published 08/2000; section Main, paragraph 2). Compounding on this, the state of the art teaches protein and antibody engineering is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number of mutations will have on an antibody or protein. Therefore, even given the sequence of an antibody, without sufficient written description of its function, the state of the art teaches its function is unpredictable. Specifically regarding antibodies, the state of the art teaches the CDR plays a key role in the target affinity of an antibody, showing that even a single amino acid alteration in the CDR can result in loss of antigen-binding function (Rudikoff, S., et al, Single amino acid substitution altering antigen-binding specificity, Proc. Natl. Acad. Sci., Vol 79, pp 1979-1983, published 03/1982; hereafter referred to as Rudikoff et al.). These references therefore teach that knowing individual CDR1-3 sequences does not enable one skilled in the art to arrive at a working combination of these CDR1-3 sequences, outside of those already known in the art. Further, even knowing the exact sequences of CDR1-3 does not enable one skilled in the art to reasonably predict its function if the exact combination of CDR1-3 is new in the art.
Because the properties and function of an antibody are highly dependent upon the amino acid sequences and exact combination of CDRs, wherein, even CDR difference or one amino acid difference in a CDR region leads to different functional properties, different conformations of CDR sequences would result in peptides having different properties. Thus, in order to demonstrate possession of the genus of single chain variable region antibodies as claimed in claim 2, one must describe a sufficient variety of species of antibody. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant disclosure and the state of the art does not teach one skilled in the art how to go from the exact combination of CDRs disclosed to the substantial variants of these CDRs combinations that would constitute representation of the broader genus of ISVD outside of the explicitly claimed sequences. As such, the disclosed species are not representative of the entire genus of anti-ADAMTS5 ISVD. In other words, knowing one combination of CDR sequences does not allow one skilled in the art to predict other functional combination of CDR sequences in this genus. It does not even allow one skilled in the art to predict whether or not having one or a combination of two CDRs known to form one functional anti-ADAMTS5 ISVD will lead to a functional anti-ADAMTS5 ISVD if the third CDR is changed.
Therefore, claim 2 is rejected for failing to provide written description of the full scope of the structures because it fails to demonstrate possession of a representative number of species within the claimed genus.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over WO ‘234 (WO2018220234A1; published 12/06/2018) in view of Balchen et al (Balchen et al, Study design of a phase I, placebo-controlled, First-in-human trial to assess safety and tolerability, immunogenicity, and pharmacokinetics and pharmacodynamics of single ascending doses of the anti-ADAMTS-5 Nanobody®, M6495, in healthy male subjects; published 04/2018).
Regarding claim 1, WO ‘234 teaches a method of treating osteoarthritis in a subject in need thereof comprising administering ADAMTS5 inhibiting polypeptide to a human subject (Abstract and page 12 line 13 – page 13 line 5).
WO ‘234 does not explicitly teach administering 75 - 300 mg of an ADAMTS5 inhibiting polypeptide.
However, WO ‘234 does teach that the dosage regimen should be determined by the physician and clinical factors, as it depends on many factors, including patient’s weight, route of administration, and other factors (page 70, lines 17-21).
Furthermore, Balchen et al teaches a registered clinical study method of treating osteoarthritis in humans comprising of administering an ADAMTS5 inhibiting polypeptide (called M6495) in doses increasing from 1 mg to 5 mg to 20 mg to 75 mg to 150 mg, and optionally to 300 mg (Methods and Figure 1). Balchen et al teaches that the lowest dose, 1 mg, is due to predicted median PD effect at ED10 (i.e. 10% of maximum effects achieved) from monkey data, and that the highest dose, 300 mg, is given if 90% of maximum effects (i.e. ED90) has not been achieved at 150 mg (Methods).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to select dosages within the dosage range disclosed by Balchen et al, especially the higher doses at and around 150 mg, as it is expected that most effects will be achieved by 150 mg, but in rare cases, 300 mg may be required.
One skilled in the art, before the effective filing date of the instant application, would be motivated to choose at least 150 mg as the dose, as it is the dose predicted to give at least 90% of maximum effects.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success as this is the dose used for another anti-ADAMTS-5 nanobody in a human clinical trial of the same disease model. Therefore, the dose must have been stringently vetted for reasonable safety and potential therapeutic effects.
Claims 2-15 depend on claim 1. The teachings of the reference(s) for claim 1 are incorporated in entirety for claims 2-15 and further discussed below, as is relevant to each claim.
Regarding claims 2-4, WO ‘234 further teaches a method wherein the ADAMTS5 inhibiting polypeptide comprises at least one immunoglobulin single variable domain (ISVD) comprising 3 complementarity determining regions (CDR), wherein the complementary determining regions are CDRl to CDR3, in which CDR1 is instant SEQ ID NO: 21, CDR2 is instant SEQ ID NO: 37, and CDR3 is instant SEQ ID NO: 55, which have a 100% amino acid sequence match to WO ‘234 CDR1 SEQ ID NO: 21, WO ‘234 CDR2 SEQ ID NO: 37, and WO ‘234 CDR3 SEQ ID NO: 55, respectively, in the anti-ADAMTS5 nanobody referred to as 02F03 (or 2F03 or 2F3) and also identified with nanobody ID number 2 (Table A-2, page 109).
WO ‘234 further teaches the exact polypeptide comprising of CDR1-3 in which CDR1 is instant/WO ‘234 SEQ ID NO: 21, CDR2 is instant/WO ‘234 SEQ ID NO: 37, and CDR3 is instant/WO ‘234 SEQ ID NO: 55 (claim 12). WO ‘234 further teaches that this nanobody (2F03) comprising of this combination of CDR1-3 is one of only three nanobodies disclosed that has an IC50 (i.e. potency) similar to a full-length monoclonal anti-ADAMTS5 antibody called mAb 12F4 used as a positive control polypeptide in their disclosed experiments (Table 5.1 on page 84, which demonstrated both structural disease modification and alleviation of pain-related behavior (page 4, lines 13-14). Further, nanobody 2F03 has the closest IC50 to mAb 12F4 (Table 5.1, page 84).
Regarding claims 5-6, WO ‘234 further teaches wherein the ISVD is amino acids 1-124 of instant SEQ ID NO: 129, as seen in the construct defined by WO ‘234 SEQ ID NO: 129 (page 108 of Table A-1) which discloses a sequence optimized version of nanobody 2F3, called nanobody 2F3*, which is the amino acids 1-124 of instant SEQ ID NO: 129, fused to a (GGGS)n linker, fused to another polypeptide.
Regarding claims 7-14, WO ‘234 further teaches wherein the ADAMTS5 inhibiting polypeptide comprises of two ISVDS, wherein the first ISVD specifically binds ADAMTS5 and is amino acids 1-124 of instant SEQ ID NO: 129 and the second ISVD binds serum albumin and is instant SEQ ID NO: 138 (page 108 of Table A-1, see construct 2F3*-A1b which is WO ‘234 SEQ ID NO: 129). Essentially, claim 14 is one embodiment of broader claims 7-13, and WO ‘234 teaches this exact embodiment of claim 14. Finally, this exact embodiment was singled out to be tested as construct 581 or “C011400581” in Figures 4-14, showing, for example, sustained inhibition of ADAMTS5/aggrecanase activity (page 90, lines 5-11 and Figure 10).
Regarding claim 15, WO ‘234 further teaches their example methods and experiments were done with assessing knee joints/cartilage as a model of osteoarthritis, but inherently, specifically knee osteoarthritis (e.g. Section 5.2 page 85 and Example 9 for bovine knee joints; Example 8 for human knee joints; Examples 11 for monkey knee joints).
Double Patenting
The USPTO may not institute a derivation proceeding in the absence of a timely filed petition. The U.S. Patent and Trademark Office normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). The applicant should amend or cancel claims such that the reference and the instant application no longer contain claims directed to the same invention.
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.
Patent No. US12209136B2
Instant claims 1-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. US12209136B2 in view of WO ‘234 (WO2018220234A1; published 12/06/2018) and further in view of Balchen et al (Balchen et al, Study design of a phase I, placebo-controlled, First-in-human trial to assess safety and tolerability, immunogenicity, and pharmacokinetics and pharmacodynamics of single ascending doses of the anti-ADAMTS-5 Nanobody®, M6495, in healthy male subjects; published 04/2018).
The instant claims are directed towards a method of treating osteoarthritis in a human subject in need thereof comprising administering 75-300 mg of an ADAMTS5 inhibiting polypeptide. Dependent claims further define the ADAMTS5 inhibiting polypeptide as comprising of specific sequences of ISVD that bind to ADAMTS5 and, in some embodiments, comprising of specific sequences of another ISVD that bind to serum albumin.
Patent ‘136 claims are directed towards a method of treating osteoarthritis in a human subject in need thereof comprising administering an ADAMTS5 inhibiting polypeptide. Dependent claims further define the ADAMTS5 inhibiting polypeptide as comprising of specific sequences of ISVD that bind to ADAMTS5 and comprising of specific sequences of another ISVD that bind to serum albumin. Patent ‘136 distinctly claim embodiments which match the embodiments of sequences or read on the genus of embodiments instantly claimed for each ISVD. For ease of comparison, it should be noted that clone 577 is the same as instant construct 581, by definition and sequence defined in the instant specification (Table A-1). Patent ‘136 claims arrive at all the ADAMTS5 inhibiting polypeptides instantly claimed and most of the limitations of the instant claims.
Patent ‘136 claims do not explicitly teach administering 75 - 300 mg of the ADAMTS5 inhibiting polypeptide.
However, WO ‘234 does teach that the dosage regimen of an ADAMTS5 inhibiting polypeptide in treating osteoarthritis should be determined by the physician and clinical factors, as it depends on many factors, including patient’s weight, route of administration, and other factors (page 70, lines 17-21).
Furthermore, Balchen et al teaches a registered clinical study method of treating osteoarthritis in humans comprising of administering an ADAMTS5 inhibiting polypeptide (called M6495) in doses increasing from 1 mg to 5 mg to 20 mg to 75 mg to 150 mg, and optionally to 300 mg (Methods and Figure 1). Balchen et al teaches that the lowest dose, 1 mg, is due to predicted median PD effect at ED10 (i.e. 10% of maximum effects achieved) from monkey data, and that the highest dose, 300 mg, is given if 90% of maximum effects (i.e. ED90) has not been achieved at 150 mg (Methods).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to select dosages within the dosage range disclosed by Balchen et al, especially the higher doses at and around 150 mg, as it is expected that most effects will be achieved by 150 mg, but in rare cases, 300 mg may be required.
One skilled in the art, before the effective filing date of the instant application, would be motivated to choose at least 150 mg as the dose, as it is the dose predicted to give at least 90% of maximum effects.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success as this is the dose used for another anti-ADAMTS-5 nanobody in a human clinical trial of the same disease model. Therefore, the dose must have been stringently vetted for reasonable safety and potential therapeutic effects.
Application No. 18983096
Instant claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18983096 (claims filed 05/02/2025) in view of WO ‘234 (WO2018220234A1; published 12/06/2018) and further in view of Balchen et al (Balchen et al, Study design of a phase I, placebo-controlled, First-in-human trial to assess safety and tolerability, immunogenicity, and pharmacokinetics and pharmacodynamics of single ascending doses of the anti-ADAMTS-5 Nanobody®, M6495, in healthy male subjects; published 04/2018). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed towards a method of treating osteoarthritis in a human subject in need thereof comprising administering 75-300 mg of an ADAMTS5 inhibiting polypeptide. Dependent claims further define the ADAMTS5 inhibiting polypeptide as comprising of specific sequences of ISVD that bind to ADAMTS5 and, in some embodiments, comprising of specific sequences of another ISVD that bind to serum albumin.
App ‘096 claims are directed towards a method of treating a disease in a human subject in need thereof comprising administering an ADAMTS5 inhibiting polypeptide. Dependent claims further define the disease to be osteoarthritis, the ADAMTS5 inhibiting polypeptide as comprising of specific sequences of ISVD that bind to ADAMTS5 and comprising of specific sequences of another ISVD that bind to serum albumin. App ‘096 distinctly claim embodiments which match the embodiments of sequences or read on the genus of embodiments instantly claimed for each ISVD. App ‘096 claims arrive at all the ADAMTS5 inhibiting polypeptides instantly claimed and most of the limitations of the instant claims.
App ‘096 claims do not explicitly teach administering 75 - 300 mg of the ADAMTS5 inhibiting polypeptide.
However, WO ‘234 does teach that the dosage regimen of an ADAMTS5 inhibiting polypeptide in treating osteoarthritis should be determined by the physician and clinical factors, as it depends on many factors, including patient’s weight, route of administration, and other factors (page 70, lines 17-21).
Furthermore, Balchen et al teaches a registered clinical study method of treating osteoarthritis in humans comprising of administering an ADAMTS5 inhibiting polypeptide (called M6495) in doses increasing from 1 mg to 5 mg to 20 mg to 75 mg to 150 mg, and optionally to 300 mg (Methods and Figure 1). Balchen et al teaches that the lowest dose, 1 mg, is due to predicted median PD effect at ED10 (i.e. 10% of maximum effects achieved) from monkey data, and that the highest dose, 300 mg, is given if 90% of maximum effects (i.e. ED90) has not been achieved at 150 mg (Methods).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to select dosages within the dosage range disclosed by Balchen et al, especially the higher doses at and around 150 mg, as it is expected that most effects will be achieved by 150 mg, but in rare cases, 300 mg may be required.
One skilled in the art, before the effective filing date of the instant application, would be motivated to choose at least 150 mg as the dose, as it is the dose predicted to give at least 90% of maximum effects.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success as this is the dose used for another anti-ADAMTS-5 nanobody in a human clinical trial of the same disease model. Therefore, the dose must have been stringently vetted for reasonable safety and potential therapeutic effects.
Application No. 18482187
Instant claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 18482187 (claims filed 02/22/2024) in view of WO ‘234 (WO2018220234A1; published 12/06/2018) and further in view of Balchen et al (Balchen et al, Study design of a phase I, placebo-controlled, First-in-human trial to assess safety and tolerability, immunogenicity, and pharmacokinetics and pharmacodynamics of single ascending doses of the anti-ADAMTS-5 Nanobody®, M6495, in healthy male subjects; published 04/2018). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed towards a method of treating osteoarthritis in a human subject in need thereof comprising administering 75-300 mg of an ADAMTS5 inhibiting polypeptide. Dependent claims further define the ADAMTS5 inhibiting polypeptide as comprising of specific sequences of ISVD that bind to ADAMTS5.
App ‘187 claims are directed towards a method of preventing a symptom or treating a disease/disorder, such as osteoarthritis, in a subject in need thereof comprising administering a polypeptide disclosed to comprise of at least one ISVD that binds to ADAMTS. Dependent claims further define the ADAMTS as ADAMTS5, and further define specific sequences of the ISVD binding ADAMTS5. App ‘187 distinctly claim embodiments which match the embodiments of sequences or read on the genus of embodiments instantly claimed for each ISVD binding ADAMTS5. For ease of comparison, it should be noted that instant CDR1-3 defined by SEQ ID NO: 21, 37, and 55, respectively, have a 100% amino acid sequence match, respectively, to App ‘187 CDR1-3, defined by SEQ ID NO: 14, 16, and 18, respectively.
App ‘187 claims do not explicitly teach administering 75 - 300 mg of the ADAMTS5 inhibiting polypeptide. App ‘187 claims do not explicitly teach the ADAMTS5 inhibiting polypeptide comprising of a second ISVD that binds serum albumin.
However, WO ‘234 teaches an ADAMTS5 inhibiting polypeptide in treating osteoarthritis comprising of a first ISVD that binds ADAMTS5, comprising of the exact CDR1-3 sequences instantly claimed and claimed by App ‘187, and a second ISVD that binds serum albumin (page 108 of Table A-1). WO ‘234 also teaches that the dosage regimen of an ADAMTS5 inhibiting polypeptide in treating osteoarthritis should be determined by the physician and clinical factors, as it depends on many factors, including patient’s weight, route of administration, and other factors (page 70, lines 17-21).
Furthermore, Balchen et al teaches a registered clinical study method of treating osteoarthritis in humans comprising of administering an ADAMTS5 inhibiting polypeptide (called M6495) in doses increasing from 1 mg to 5 mg to 20 mg to 75 mg to 150 mg, and optionally to 300 mg (Methods and Figure 1). Balchen et al teaches that the lowest dose, 1 mg, is due to predicted median PD effect at ED10 (i.e. 10% of maximum effects achieved) from monkey data, and that the highest dose, 300 mg, is given if 90% of maximum effects (i.e. ED90) has not been achieved at 150 mg (Methods).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to include an ISVD that binds to serum albumin, and specifically the already validated serum albumin-binding ISVD provided by WO ‘234, as ISVDs that bind serum albumin is well-known in the art for their use in extending the serum half-life of the therapeutic construct it is attached to, especially small constructs, such as ISVD, that could typically be quickly cleared from serum. It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to select dosages within the dosage range disclosed by Balchen et al, especially the higher doses at and around 150 mg, as it is expected that most effects will be achieved by 150 mg, but in rare cases, 300 mg may be required.
One skilled in the art, before the effective filing date of the instant application, would be motivated to extend the half-life of a therapeutic construct. One skilled in the art, before the effective filing date of the instant application, would be motivated to choose at least 150 mg as the dose, as it is the dose predicted to give at least 90% of maximum effects.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success since binding to serum albumin is a well-known method of extending serum half-life of small therapeutic constructs. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success as this is the dose used for another anti-ADAMTS-5 nanobody in a human clinical trial of the same disease model. Therefore, the dose must have been stringently vetted for reasonable safety and potential therapeutic effects.
Conclusion
No claims are allowed.
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/B.C./Examiner, Art Unit 1645 March 4, 2026
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645