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 .
DETAILED ACTION
Applicant’s amendment and response filed 9/5/24 is acknowledged and has been entered. Claims 1 and 18 are independent claims.
Claim interpretation: The specification discloses that “Osteoarthritis” as used herein, refers to a type of arthritis that involves wear-and-tear damage to a joint’s cartilage ([0042]). The specification discloses that the terms “reduce, “inhibit” and “block” refer to any statistically significant decrease in biological activity such as hemichannel opening ([0045]). The specification discloses that the term “about” or “approximately” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15% compared to a reference ([0028]). The specification discloses that “treatment” refers to therapeutic treatment, and osteoarthritis is inhibited or treated if at least one symptom of the condition is alleviated, terminated, slowed, minimized, or prevented ([0093]), and that treatment can be administered to subjects having, suffering from, susceptible to, or at risk of developing osteoarthritis ([0095]). The specification discloses that the term “subject” or “patient” refers to either a human or a non-human ([0094]). The specification discloses that the term “effective amount” refers to the amount of an agent which is sufficient to effect treatment, prognosis or diagnosis of osteoarthritis when administered to a patient or a subject ([0097]). The specification discloses that the term “antibody” is used in the broadest sense and includes full length antibody, antibody peptides or immunoglobulins, mAbs, chimeric, human or humanized antibodies, polyclonal antibodies, antibodies from non-human species, including from human Ig germline transduced, and individual antigen binding fragments thereof ([0046]). The specification discloses that the anti-Cx43 antibody can be any antibody [that] specifically binds Cx43 ([0065]). The specification discloses that Cx43 is 382 amino acid residues in length and corresponds to NCBI Reference Sequence: NP000156 ([0092]). The specification discloses that “As used herein, the term “specifically binds” is not intended to indicate that an antibody binds exclusively to its intended target. Rather, an antibody “specifically binds” if its affinity for its intended target is about 5-fold greater when compared to its affinity for a non-target molecule. Suitably there is no significant cross-reaction or cross-binding with undesired substances.” (See [0039]).
3. 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.
4. Claims 18, 20, 24, 25, 27, 30-32 and 34 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. This is a written description rejection.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
Applicant has broadly claimed a method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject an effective amount of an anti-connexin 43 (Cx43) antibody, wherein the anti-Cx43 antibody is administered according to the recited dosage schedule, and including the limitations of the dependent claims.
As such the antibody recited in the claimed method must possess the functional property of specifically binding to Cx43 (see claim interpretation section above in this office action) and in claim 34, it must also possess the functional property of blocking the opening of Cx43 hemichannel in the subject. The antibody recited in the method of claims in claims 18, 20, 24, 25, 27 and 34 are recited for its binding specificity and the aforementioned functional properties. The antibody recited in the method of claims 31 and 32 also must possess the functional property of specifically binding to Cx43 but may only comprise one of a defined VH or VL due to the recitation of “and/or” separating the VH and VL sequences in said claims, a recitation by function and partial structure.
The specification does not disclose a representative number of species of such antibody to be administered in the claimed method of treating osteoarthritis in a subject, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function. This is the case for the following reasons.
As Applicant is undoubtedly aware, recent court decisions in the biotechnology arena have highlighted the issue with defining binding members strictly using functional terms as can be readily seen in both AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) and Amgen v. Sanofi. (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim a binding molecule by describing something that is not the invention, i.e., the structure to which it binds, as knowledge of the chemical structure of the thing being bound does not give the required kind of structure-identifying information about the thing being claimed.
The recitation of the antigen to which an antibody binds does not provide adequate written description for the genus of such antibodies.
The antibodies recited in the instant claims encompass any species of animal that can make them or encompasses artificial repertoires of antibodies. It is known in the art that the repertoires of antibodies that bind to a same antigen or epitope from different species are highly diverse, both within the species repertoire and between species (see for example, Lloyd et al. (Protein Engineering, Eng. Design & Selection, 2009, 22(3): 159-168), Edwards et al. (JMB, 2008, 334: 103-118), Poosarla et al. (Biotechn. Bioeng., 2017, 114(6): 1331-1342), Khan and Salunke (J. Immunol, 2014, 192: 5398-5405)). For example, the CDR repertoires of rabbit and mouse antibodies that bind to the same antigen or epitope are significantly different in their germline genetics, average loop lengths and somatic diversification mechanisms, even when convergent to recognize identical molecular features on a target. In addition, mice diversify their repertoires primarily through VDJ combinatorial joining and random addition/deletion at junctions, whereas rabbit rely heavily on gene conversion using upstream pseudogenes in tandem with very high rates of somatic hypermutation. Camelids and sharks make single chain antibodies.
The instant specification discloses a single set of cognate CDRs and VH corresponding to SEQ ID NO: 7 and VL corresponding to SEQ ID NO: 8 (see Table 7). An inspection of the heavy chains corresponding to SEQ ID NO: 9, 12,16 and 18 reveals that all possess the CDRS and VH regions present in SEQ ID NO: 7, while the HCDR2 of SEQ ID NO: 11, 13-15 and 17 differ from that found in the SEQ ID NO: 7, and differs from SEQ ID NO: 7, at only one amino acid residue (i.e., INPSNAGT vs INPSNGGT). The specification discloses that SEQ ID NO: 7/8 are comprised in monoclonal antibody ALMB-0166 and this antibody was used in the examples of treating a rat model of osteoarthritis. The specification does not disclose which species of antibody the antibody was made in. The specification therefore has disclosed two species of antibody CDRs that are closely related (differing in just one amino acid residue in one CDR) that was made in one species of animal. This speaks to the lack of a representative number of species of such antibodies to be administered in the claimed method.
As pertains to the claims reciting only one of a VH or a VL, is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. One of skill in the art could not readily envision the sequence of other CDRs, VHs or VLs that can be comprised within the antibody possessing only one of the recited VH or VL.
Evidentiary reference US 12,227,561 discloses anti-Cx43 antibodies that activate and open connexin43 hemichannels, e.g., for treating cancer, osteosarcoma, osteoporosis, or osteopenia. Note that an exemplary antibody disclosed therein has the same VH CDRs1-3 and the same light chain CDR1 as are recited in the instant claims yet has the opposite function to that required by the instant claims (see entire reference, especially abstract, claims, column 10 at lines 43-61).
As such, artisans would reasonably conclude that Applicant was not in possession of the genus of all anti-Cx43 antibodies at the time the instant application was filed and therefore logically could not have been in possession of the claimed method using said antibodies at the time the instant invention was filed.
5. Claims 18, 20, 24, 25, 27, 30-32 and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
“To be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech, Inc. v. Novo Nordisk, A/S, 108F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997) (quoting In re Wright, 999F2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)). In In re Wands 8 USPQ2d 1400 (CAFC 1988), a number of factors are set forth which a court may consider in determining whether a disclosure would require undue experimentation. These factors were set forth as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. All the factors need not be reviewed when determining whether a disclosure is enabling. Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927F2.d 1200, 1213, 18 USPQ2d 1016, 1027 (Fed. Cir. 1991) (noting that the Wands factors “are illustrative, not mandatory. What is relevant depends upon the facts.”).
The specification does not disclose how to make and use the instant invention, a method for treating osteoarthritis in a subject in need thereof comprising administering to the subject an effective amount of an anti-connexin 43 (CX43) antibody administered in the recited dosage regimen, and including the limitations recited in the dependent claims,
The state of the art is such that it is unpredictable in the absence of appropriate evidence whether the claimed
Regarding the Wands factors and the state of the art, the skilled artisan was aware that it is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. It has been known for quite some time that even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA 1982 Vol 79 pages 1979-1983).
For example, evidentiary reference D’Angelo et al. (Front. Immunol. 2018, 9, article 395, pages 1-13) teaches that “the same HCDR3 can be generated by many different rearrangements, but that specific target binding is an outcome of unique rearrangements and VL pairing: the HCDR3 is necessary, albeit insufficient for specific antibody binding” (see entire reference, especially abstract).
De Pascalis et al. (The Journal of Immunology (2002) 169: 3076-3084) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.).
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (BBRC, 2003, 307: 198-205) who constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.).
Holm et al. (Molecular Immunol. 2007, 44, 1075-1084) describes the mapping of an anti-cytokeratin antibody where although residues in the CDR3 of the heavy chain were involved in antigen binding while a residue in CDR2 of the light chain was also involved (abstract).
The instant specification discloses in the Examples that ALMB-0166 (i.e., presumably comprising a VH corresponding to SEQ ID NO: 7 and a VL corresponding to SEQ ID NO: 8 as well as the CDRS corresponding to SEQ ID NO: 1-6) treats osteoarthritis in a rat model (SEQ ID NO: 7 is also comprised in SEQ ID NO: 9, 12, 16 and 18, while SEQ ID NO: 8 is also comprised in SEQ ID NO: 10). The specification has not disclosed the VH and VL corresponding to ALMB-0166, nor the constant regions thereof.
Evidentiary reference CSPC Pharmaceutical Group (12/29/2022, 2 pages) teaches that ALMB-0166 has gained clinical trial approval for treatment of osteoarthritis. The said reference further teaches that ALMB-0166 is a first-in-class humanized monoclonal antibody antagonist for the novel target hemichannel Connexin 43 membrane protein (see entire reference).
Evidentiary reference AlaMab teaches that ALMB-0166 inactivates connexin43 hemichannels causing them to close (see last paragraph on the second-to-last page).
Neither the instant specification, nor the art, disclose the sequence of ALMB-0016.
The specification does not disclose any other species of antibody that treats osteoarthritis, nor does the specification disclose the VL and corresponding CDRs that pair with one of the recited VHs, nor does it disclose the VH and corresponding CDRs that pair with the one recited VL, except for those recited in the claims.
Evidentiary reference US 12,227,561 discloses anti-Cx43 antibodies that activate and open connexin43 hemichannels, e.g., for treating cancer, osteosarcoma, osteoporosis, or osteopenia. Note that an exemplary antibody disclosed therein has the same VH CDRs1-3 and the same light chain CDR1 as are recited in the instant claims yet has the opposite function to that required by the instant claims to effect treatment of osteoarthritis (see entire reference, especially abstract, claims, column 10 at lines 43-61).
There is insufficient guidance in the specification as to how to use the instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
6. 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.
7. 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.
8. Claims 1, 2, 6, 10, 15-18, 20, 24 and 29-34 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by WO2020/163353 A1.
Instant base claim 1 recites: A method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject at least one dose of an anti-connexin 43 (Cx43) antibody, wherein the anti-Cx43 antibody comprises heavy chain CDRS and light chain CDR sequences corresponding to SEQ ID NO: 1-6, respectively.
Instant base claim 18 recites: A method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject an effective amount of an anti-connexin 43 (Cx43) antibody, wherein the anti-CX43 antibody is administered according to the recited dosages in the recited sequences (i.e., weekly intervals of first through fourth doses).
WO2020/163353 A1 teaches treating osteoarthritis with a composition comprising an effective amount of an anti-Cx43 antibody or antigen-binding fragment thereof, wherein the osteoarthritis is associated with opening of Cx43 hemichannels, wherein the antibody comprises the HCDRs of SEQ ID NO: 1-3 and the LCDRs of SEQ ID NO: 4-6 (which are identical to instantly recited SEQ ID NO: 1-6, see page 15 at lines 25-35 of the art reference). WO2020/163353 A1 teaches that the VH may correspond to SEQ ID NO: 7 and the VL corresponds to SEQ ID NO: 8 (which are identical to instantly recited SEQ ID NO: 7 and 8, respectively; see page 16 at lines 17-24 of the art reference). The antibody or antigen-binding fragment thereof may comprise a heavy chain having an amino acid sequence selected from SEQ ID NO: 9-17 and a light chain having the amino acid sequence of SEQ ID NO: 18 (e.g., page 4 at lines 8-10 and 15-33). WO2020/163353 A1 teaches that SEQ ID NO: 9 is the heavy chain of Ab#C (that is identical to instantly recited SEQ ID NO: 14 and has an “N” rather than an “A” in HCDR2 at the third to last position thereof, see sequence spanning pages 16-17). WO2020/163353 A1 teaches that SEQ ID NO: 10 is the heavy chain of Ab#E (identical to SEQ ID NO: 11 of the instant application that also has the “N” substituent amino acid residue at HCDR2). WO2020/163353 A1 teaches that SEQ ID NO: 11 is the heavy chain of Ab#G (has the SEQ ID NO: 1-6 CDRs and comprises SEQ ID NO: 7), SEQ ID NO: 12 is the heavy chain of Ab#I (that is identical to SEQ ID NO: 13 of the instant application and also has the HCDR2 “N” substituent amino acid residue), SEQ ID NO: 13 is the heavy chain of Ab#K (that is identical to instantly recited SEQ ID NO: 9 and has the SEQ ID NO: 1-6 CDRs and comprises SEQ ID NO: 7), SEQ ID NO: 14 is the heavy chain of Ab#M and SEQ ID NO: 16 is the heavy chain of Ab#Q (which are identical to SEQ ID NO: 15 and 17, respectively, and both have the HCDR2 “N” substituent amino acid residue), SEQ ID NO: 15 is the heavy chain of Ab#O and SEQ ID NO: 17 is the heavy chain of Ab#S (which are identical to instantly recited SEQ ID NO: 16 and 18, respectively) (see pages 17-18 of the art reference). SEQ ID NO: 18 is the light chain (see page 19 at lines 4-8) (which is identical to instantly recited SEQ ID NO: 10). WO2020/163353 A1 teaches that exemplary dosage ranges for administration include 10-1000 mg antibody/kg of body weight or at a dose of between 0.1 mg/kg to about 100 md/kg body weight (page 37 at lines 1-5), while dosage schedules can include once every three days to once every five days, once every week, once every 10 days, once every two weeks, once every three weeks and once a month (e.g., paragraph spanning pages 31-32), although dosage levels may be varied to achieve the desired therapeutic response for a particular patient (page 32 at lines 14-17), and the frequency of multiple sequential doses of an antibody may be administered to a subject over a defined time course (paragraph spanning pages 34-35, page 35-page 36 at line 20). WO2020/163353 A1 teaches that an effective amount is the amount of the antibody which is sufficient to effect treatment of a disease and will vary depending upon the patient and condition being treated (paragraph spanning pages 10-11). Administration may be intravenous (page 34 at lines 14-22) and the patient may be a human (page 35 at lines 20-21, page 12 at lines 15-23). See entire reference including claims. Please note that as instant claims 18, 20, 24 and 34 do not recite any particular CDR, VH, or VL sequences, the antibodies that have the “N” in HCDR2 (as well as those that do have identical CDRs to that recited in claims 1 and its dependent claims and claim 29) qualify as prior art against these said claims.
9. Claims 1, 2, 6, 10, 15-18, 20, 24 and 29-34 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by US 2022/0033492 A1.
Instant base claim 1 recites: A method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject at least one dose of an anti-connexin 43 (Cx43) antibody, wherein the anti-Cx43 antibody comprises heavy chain CDRS and light chain CDR sequences corresponding to SEQ ID NO: 1-6, respectively.
US 2022/0033492 A1 discloses treating an inflammatory disease such as osteoarthritis in a human with a pharmaceutical composition comprising an antibody that has the same CDRs, VH and VL as those that are recited in the instant claims, wherein the method inhibits opening of Cx43 hemichannels (e.g., abstract, [0151], [0154], [0159], claims). Please note that SEQ ID NO: 18 of the art reference is identical to instantly recited SEQ ID NO: 10. The following are the concordances for other recited sequences:
US2022/0033492 A1 instant claims
SEQ ID NO: 11 SEQ ID NO: 12
SEQ ID NO: 13 SEQ ID NO: 9
SEQ ID NO: 15 SEQ ID NO: 16
SEQ ID NO: 17 SEQ ID NO: 18.
US 2022/0033492 A1 further discloses that the term “effective amount” refers to that amount of an anti-Cx43 antibody sufficient to effect treatment of a disease when administered, with dosages ranging from about 1 ng to about 10,000 mg, with IV administration, and weekly administration, with concentration per dose at about 6-24 mg/kg weight (e.g., [0082]). See entire reference.
10. 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.
11. Claims 1, 2, 6, 10, 11, 13, 15-18, 20, 24, 25, 27 and 29-34 are rejected under 35 U.S.C. 103 as being unpatentable over WO2020/163353 A1 in view of Tiseo et al. (PAIN, 2014, 155: 1245-1252).
Instant base claim 1 recites: A method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject at least one dose of an anti-connexin 43 (Cx43) antibody, wherein the anti-Cx43 antibody comprises heavy chain CDRS and light chain CDR sequences corresponding to SEQ ID NO: 1-6, respectively.
Instant base claim 18 recites: A method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject an effective amount of an anti-connexin 43 (Cx43) antibody, wherein the anti-CX43 antibody is administered according to the recited dosages in the recited sequences (i.e., weekly intervals of first through fourth doses).
WO2020/163353 A1 teaches treating osteoarthritis with a composition comprising an effective amount of an anti-Cx43 antibody or antigen-binding fragment thereof, wherein the osteoarthritis is associated with opening of aCx43 hemichannels, wherein the antibody comprises the HCDRs of SEQ ID NO: 1-3 and the LCDRs of SEQ ID NO: 4-6 (which are identical to instantly recited SEQ ID NO: 1-6, see page 15 at lines 25-35 of the art reference). WO2020/163353 A1 teaches that the VH may correspond to SEQ ID NO: 7 and the VL corresponds to SEQ ID NO: 8 (which are identical to instantly recited SEQ ID NO: 7 and 8, respectively; see page 16 at lines 17-24 of the art reference). The antibody or antigen-binding fragment thereof may comprise a heavy chain having an amino acid sequence selected from SEQ ID NO: 9-17 and a light chain having the amino acid sequence of SEQ ID NO: 18 (e.g., page 4 at lines 8-10 and 15-33). WO2020/163353 A1 teaches that SEQ ID NO: 9 is the heavy chain of Ab#C (that is identical to instantly recited SEQ ID NO: 14 and has an “N” rather than an “A” in HCDR2 at the third to last position thereof, see sequence spanning pages 16-17). WO2020/163353 A1 teaches that SEQ ID NO: 10 is the heavy chain of Ab#E (identical to SEQ ID NO: 11 of the instant application that also has the “N” substituent amino acid residue at HCDR2). WO2020/163353 A1 teaches that SEQ ID NO: 11 is the heavy chain of Ab#G (has the SEQ ID NO: 1-6 CDRs and comprises SEQ ID NO: 7), SEQ ID NO: 12 is the heavy chain of Ab#I (that is identical to SEQ ID NO: 13 of the instant application and also has the HCDR2 “N” substituent amino acid residue), SEQ ID NO: 13 is the heavy chain of Ab#K (that is identical to instantly recited SEQ ID NO: 9 and has the SEQ ID NO: 1-6 CDRs and comprises SEQ ID NO: 7), SEQ ID NO: 14 is the heavy chain of Ab#M and SEQ ID NO: 16 is the heavy chain of Ab#Q (which are identical to SEQ ID NO: 15 and 17, respectively, and both have the HCDR2 “N” substituent amino acid residue), SEQ ID NO: 15 is the heavy chain of Ab#O and SEQ ID NO: 17 is the heavy chain of Ab#S (which are identical to instantly recited SEQ ID NO: 16 and 18, respectively) (see pages 17-18 of the art reference). SEQ ID NO: 18 is the light chain (see page 19 at lines 4-8) (which is identical to instantly recited SEQ ID NO: 10). WO2020/163353 A1 teaches that exemplary dosage ranges for administration include 10-1000 mg antibody/kg of body weight or at a dose of between 0.1 mg/kg to about 100 md/kg body weight (page 37 at lines 1-5), while dosage schedules can include once every three days to once every five days, once every week, once every 10 days, once every two weeks, once every three weeks and once a month (e.g., paragraph spanning pages 31-32), although dosage levels may be varied to achieve the desired therapeutic response for a particular patient (page 32 at lines 14-17), and the frequency of multiple sequential doses of an antibody may be administered to a subject over a defined time course (paragraph spanning pages 34-35, page 35-page 36 at line 20). WO2020/163353 A1 teaches that an effective amount is the amount of the antibody which is sufficient to effect treatment of a disease and will vary depending upon the patient and condition being treated (paragraph spanning pages 10-11). Administration may be intravenous (page 34 at lines 14-22) and the patient may be a human (page 35 at lines 20-21, page 12 at lines 15-23). See entire reference including claims.
WO2020/163353 A1 does not teach wherein at least one indicator of osteoarthritis severity is assessed at least one day to one week after each dose is administered (claims 11 and 25), wherein the at least on indicator of osteoarthritis severity is improves after at least one does of the anti-Cx43 antibody administration (claims 13 and 27).
Tiseo et al. teach administration of an antibody to osteoarthritis patients, wherein pain intensity was recorded daily after administration and subscales for pain, stiffness and function were completed at baseline and at weeks 1, 2, 4, 8, 10, 12, 16, 20 and 25, with all administration at all chosen doses associated with greater improvement in walking knee pain as compared to placebo (see entire reference, including abstract and study assessments section 2.3, and efficacy section 3.2).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have assessed at least one indicator of osteoarthritis severity at least one day to one week after dose administration, and to choose a dose that improves severity.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to assess the effects of administration in real time and to adjust dosages if needed for particular patients.
12. Claims 1, 2, 6, 10, 11, 13, 15-18, 20, 24, 25, 27 and 29-34 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0033492 A1 in view of Tiseo et al. (PAIN, 2014, 155: 1245-1252).
The disclosure of US 2022/0033492 A1 has been enunciated above and will not be repeated herein. US 2022/0033492 A1 additionally discloses that the most common symptoms are joint pain and stiffness [0159].
US 2022/0033492 A1 does not disclose wherein an indicator of osteoarthritis severity is assessed at least one day to one week after each does is administered, nor wherein the at least one indicator is improved after the at least one dose (claims 11, 13, 25 and 27).
Tiseo et al. teach administration of an antibody to osteoarthritis patients, wherein pain intensity was recorded daily after administration and subscales for pain, stiffness and function were completed at baseline and at weeks 1, 2, 4, 8, 10, 12, 16, 20 and 25, with all administration at all chosen doses associated with greater improvement in walking knee pain as compared to placebo (see entire reference, including abstract and study assessments section 2.3, and efficacy section 3.2).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have assessed at least one indicator of osteoarthritis severity at least one day to one week after dose administration, and to choose a dose that improves severity.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to assess the effects of administration in real time and to adjust dosages if needed for particular patients.
13. Claims 18, 20, 24, 30 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over US 10,663,442.
Instant base claim 18 recites: A method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject an effective amount of an anti-connexin 43 (Cx43) antibody, wherein the anti-CX43 antibody is administered according to the recited dosages in the recited sequences (i.e., weekly intervals of first through fourth doses).
Please note that the instant claims do not recite any particular CDR, VH, or VL sequences.
US 10,633,442 discloses that agents that block the opening of Cx43 hemichannels can be used as a therapeutic to treat inflammatory disorders such as OA (i.e., osteoarthritis) (e.g., column 14 at lines 2-4, column 13 at lines 63-65). US 10,633,442 discloses an antibody that binds Cx43 that comprises SEQ ID NO: 2 (VH) and SEQ ID NO: 4 (VL) of the art reference (e.g., claim 3) that inhibits the opening of a Cx43 hemichannel in a subject (e.g., claim 19). See entire reference, including claims.
As regards the dosing regimen recited in the instant claims, these limitations constitute result- effective variables well within the purview of one of ordinary skill in the art to determine.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have administered the said antibody in order to treat osteoarthritis and to have determined the optimal dosage regimen in terms of administration days, number of administrations, and mg/kg of body weight dosages to administer.
One of ordinary skill would have been motivated to do this, and with a reasonable expectation of success in doing so, as the art reference discloses that an agent that can block the opening of a Cx43 hemichannel can be used as a therapeutic to treat osteoarthritis, and teaches such an antibody that can inhibit the opening of a Cx43 hemichannel.
(Please note as a side issue that SEQ ID NO: 2 of the art reference comprises all of the same HCDRs as SEQ ID NO: 7 of the instant application but for a one amino acid change, that of G for A in HCDR2 (i.e., INPSNGNT versus INPSNAGT) and has overall 82% sequence identity thereto and that SEQ ID NO: 4 of the art reference has about 68% sequence identity with SEQ ID NO: 8 of the instant application. This is:
EMBOSS_001 1 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMYWVRQAPGQGLEWIGG 50
||||.|.|||:.|||||||:|||||||||||||||||:|.||||||||||
EMBOSS_001 1 EVQLEQPGAELVKPGASVKLSCKASGYTFTSYYMYWVKQRPGQGLEWIGG 50
EMBOSS_001 51 INPSNAGTNFNEKFKNRATLTVDKSTSTAYMELSSLRSEDTAVYYCTREG 100
|||||.||||||||||:||||||||:|||||:||||.|||:|||||||||
EMBOSS_001 51 INPSNGGTNFNEKFKNKATLTVDKSSSTAYMQLSSLTSEDSAVYYCTREG 100
EMBOSS_001 101 NPYYTMNYWGQGTLVTVSS--------- 119 instant SEQ ID NO: 7
|||||||||||||.|||||
EMBOSS_001 101 NPYYTMNYWGQGTSVTVSSAKTTPPSVY 128 art SEQ ID NO: 2; and
EMBOSS_001 1 DIVMTQSPDSLAVSLGERATISCKSSQSLLNSGNQKTYLAWYQQKPGQPP 50
||||||:|.|||||||:|||||.::|:|:..|| .:|:.|.||||||||
EMBOSS_001 1 DIVMTQTPASLAVSLGQRATISYRASKSVSTSG--YSYMHWNQQKPGQPP 48
EMBOSS_001 51 KLLIYGASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDHSY 100
:||||..|..|||||.|||||||||||||.|..::.||.|.|||| |..
EMBOSS_001 49 RLLIYLVSNLESGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQ--HIR 96
EMBOSS_001 101 PFTFGQG---TKLEIK 113 instant SEQ ID NO: 8
..|..:| .|
EMBOSS_001 97 ELTRSEGGPSWK---- 108 art SEQ ID NO: 4
14. Claims 25 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over US 10,663,442 as applied to claims 18, 20, 24, 30 and 34 above, and further in view of Tiseo et al. (PAIN, 2014, 155: 1245-1252).
US 10,663,442 does not teach wherein at least one indicator of osteoarthritis severity is assessed at least one day to one week after each dose is administered (claim 25), wherein the at least on indicator of osteoarthritis severity is improves after at least one does of the anti-Cx43 antibody administration (claim 27).
Tiseo et al. teach administration of an antibody to osteoarthritis patients, wherein pain intensity was recorded daily after administration and subscales for pain, stiffness and function were completed at baseline and at weeks 1, 2, 4, 8, 10, 12, 16, 20 and 25, with all administration at all chosen doses associated with greater improvement in walking knee pain as compared to placebo (see entire reference, including abstract and study assessments section 2.3, and efficacy section 3.2).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have assessed at least one indicator of osteoarthritis severity at least one day to one week after dose administration, and to choose a dose that improves severity.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to assess the effects of administration in real time and to adjust dosages if needed for particular patients.
15. 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.
16. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 17/767,171 case that issued as US 12,187,794 as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 1, 2, 6, 10, 15-18, 20, 24 and 29-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,187,794.
Claims 1-10 are drawn to an anti-Cx43 antibody or antigen binding fragment thereof having the same CDRs as are recited in the instant claims as well as the same VH/VL, and pharmaceutical composition thereof for inhibiting opening of Cx43 hemichannels in cells. Please note that SEQ ID NO: 18 of the claims of ‘794 is identical to instantly recited SEQ ID NO: 10. The following are the concordances for other recited sequences:
‘794 instant claims
SEQ ID NO: 11 SEQ ID NO: 12
SEQ ID NO: 13 SEQ ID NO: 9
SEQ ID NO: 15 SEQ ID NO: 16
SEQ ID NO: 17 SEQ ID NO: 18.
The claims of US 12,187,794 do not recite wherein the pharmaceutical is for treating osteoarthritis, i.e., for the condition for which inhibiting opening of Cx43 channels is desired, nor wherein the pharmaceutical composition is administered to treat osteoarthritis.
WO2020/163353 A1 teaches treating osteoarthritis with a composition comprising an effective amount of an anti-Cx43 antibody or antigen-binding fragment thereof, wherein the osteoarthritis is associated with opening of Cx43 hemichannels, wherein the CDRs are the same CDRs (SEQ ID NO: 1-6), VH (SEQ ID NO: 7), and VL (SEQ ID NO: 8), as is enunciated above in detail in this office action. The full teachings of WO2020/163353 A1 are enunciated above in this office action and will not be repeated herein except to state that the dosing amounts and concentrations taught by the art reference fall into or overlap the ranges recited in the instant claims, and the art reference teaches treating osteoarthritis with the same antibodies.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used the pharmaceutical composition with the intended use of inhibiting opening of Cx43 hemichannels recited in the claims of US 12,187,794 to treat osteoarthritis as is taught by WO2020/163353 A1.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, as WO2020/163353 A1 teaches using the same antibody to treat osteoarthritis which can treat osteoarthritis as it is associated with opening of Cx43 hemichannels.
17. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 17/390,635 case that issued as US 11,912,276 as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 1, 2, 6, 10, 15-18, 20, 24 and 29-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,912,764.
Claims 1-17 19 and 20 of US 11,912,764 are drawn to a pharmaceutical formulation comprising an anti-Cx43 antibody or antigen binding fragment thereof having the same CDRs as are recited in the instant claims as well as the same VH/VL. Please note that SEQ ID NO: 18 of the claims of ‘276 is identical to instantly recited SEQ ID NO: 10. The following are the concordances for other recited sequences:
‘276 instant claims
SEQ ID NO: 11 SEQ ID NO: 12
SEQ ID NO: 13 SEQ ID NO: 9
SEQ ID NO: 15 SEQ ID NO: 16
SEQ ID NO: 17 SEQ ID NO: 18.
Claim 18 of US 11,912,764 is drawn to a method of inhibiting opening of Cx43 hemichannels in cells comprising administering the said pharmaceutical formulation for treating an inflammatory disease or condition, or a neurodegenerative disease.
The claims of US 11,912,764 do not recite wherein the pharmaceutical is for treating osteoarthritis, i.e., for the condition for which inhibiting opening of Cx43 channels is desired, nor wherein the pharmaceutical composition is administered to treat osteoarthritis.
WO2020/163353 A1 teaches treating osteoarthritis with a composition comprising an effective amount of an anti-Cx43 antibody or antigen-binding fragment thereof, wherein the osteoarthritis is associated with opening of Cx43 hemichannels, wherein the CDRs are the same CDRs (SEQ ID NO: 1-6), VH (SEQ ID NO: 7), and VL (SEQ ID NO: 8), as is enunciated above in detail in this office action. The full teachings of WO2020/163353 A1 are enunciated above in this office action and will not be repeated herein except to state that the dosing amounts and concentrations taught by the art reference fall into or overlap the ranges recited in the instant claims.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used the pharmaceutical composition with the intended use of inhibiting opening of Cx43 hemichannels recited in the claims of US 11,912,764 to treat osteoarthritis as is taught by WO2020/163353 A1.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, as WO2020/163353 A1 teaches using the same antibody to treat osteoarthritis which can treat osteoarthritis as it is associated with opening of Cx43 hemichannels.
18. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/415,511 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 18, 20, 24, 25, 27, 30-32 and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No 18/415,511 in view of WO2020/163353 A1 and Tiseo et al. (PAIN, 2014, 155: 1245-1252).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Please note that the instant claims do not recite any particular sequences for the anti-Cx43 antibody.
Claims 1-19 of 18/415,511 are drawn to a pharmaceutical formulation comprising an anti-Cx43 antibody or antigen binding fragment thereof, the antibody comprising a heavy chain variable domain having the amino acid sequence of amino acids 1-119 of SEQ ID NO: 9, 10, 12, 14, or 16 (anti-Cx43 antibodies having the HCDR2 INPSNGGT sequence, rather than the INPSNAGT sequence that is recited in instant claim 1) and LCDRs corresponding to SEQ ID NO: 4-6 (that are identical to SEQ ID NO: 4-6 of the instant application), and the light chain may have the amino acid sequence of SEQ ID NO: 8 (which is identical to instant SEQ ID NO: 10) (see Table 39 in the specification of 18/415,511). The antibody is present at a concentration of between about 5 and 100 mg/ml. The antibody binds the same epitope as the antibody of the instant application, i.e., SEQ ID NO: 19 of both 18/415,511 and of the instant application).
Claim 20 of 18/415,511 is drawn to a method of inhibiting opening of Cx43 hemichannels in cells comprising administering the said pharmaceutical formulation, preferably for treating an inflammatory disease or condition. The specification of 18/415,511 evidences that osteoarthritis is such an inflammatory disease or condition (see for example, paragraph spanning pages 26-27).
The claims of 18/415,511 do not recite the administration protocol in weekly doses, the amount of antibody/kg of weight, nor that the antibody is administered IV, nor that the inflammatory condition is osteoarthritis (although the specification of ‘511 does disclose that osteoarthritis is such an inflammatory condition, see for example the specification of ‘511 at page 19, lines 7-9).
WO2020/163353 A1 teaches a number of anti-Cx43 antibodies that have the same CDRs as are recited in the claims of 18/415,511 that bind to the same epitope and may be used for treating osteoarthritis. WO2020/163353 A1 teaches weekly administration, dosage ranges falling within or overlapping those that are instantly recited, and that the antibody may be administered by the IV route:
WO2020/163353 A1 teaches treating osteoarthritis with a composition comprising an effective amount of an anti-Cx43 antibody or antigen-binding fragment thereof, wherein the osteoarthritis is associated with opening of Cx43 hemichannels, wherein the antibody comprises the HCDRs of SEQ ID NO: 1-3 and the LCDRs of SEQ ID NO: 4-6 (which are identical to instantly recited SEQ ID NO: 1-6, see page 15 at lines 25-35 of the art reference). WO2020/163353 A1 teaches that the VH may correspond to SEQ ID NO: 7 and the VL corresponds to SEQ ID NO: 8 (which are identical to instantly recited SEQ ID NO: 7 and 8, respectively; see page 16 at lines 17-24 of the art reference). The antibody or antigen-binding fragment thereof may comprise a heavy chain having an amino acid sequence selected from SEQ ID NO: 9-17 and a light chain having the amino acid sequence of SEQ ID NO: 18 (e.g., page 4 at lines 8-10 and 15-33). WO2020/163353 A1 teaches that SEQ ID NO: 9 is the heavy chain of Ab#C (that is identical to instantly recited SEQ ID NO: 14 and has an “N” rather than an “A” in HCDR2 at the third to last position thereof, see sequence spanning pages 16-17). WO2020/163353 A1 teaches that SEQ ID NO: 10 is the heavy chain of Ab#E (identical to SEQ ID NO: 11 of the instant application that also has the “N” substituent amino acid residue at HCDR2). WO2020/163353 A1 teaches that SEQ ID NO: 11 is the heavy chain of Ab#G (has the SEQ ID NO: 1-6 CDRs and comprises SEQ ID NO: 7), SEQ ID NO: 12 is the heavy chain of Ab#I (that is identical to SEQ ID NO: 13 of the instant application and also has the HCDR2 “N” substituent amino acid residue), SEQ ID NO: 13 is the heavy chain of Ab#K (that is identical to instantly recited SEQ ID NO: 9 and has the SEQ ID NO: 1-6 CDRs and comprises SEQ ID NO: 7), SEQ ID NO: 14 is the heavy chain of Ab#M and SEQ ID NO: 16 is the heavy chain of Ab#Q (which are identical to SEQ ID NO: 15 and 17, respectively, and both have the HCDR2 “N” substituent amino acid residue), SEQ ID NO: 15 is the heavy chain of Ab#O and SEQ ID NO: 17 is the heavy chain of Ab#S (which are identical to instantly recited SEQ ID NO: 16 and 18, respectively) (see pages 17-18 of the art reference). SEQ ID NO: 18 is the light chain (see page 19 at lines 4-8) (which is identical to instantly recited SEQ ID NO: 10). WO2020/163353 A1 teaches that exemplary dosage ranges for administration include 10-1000 mg antibody/kg of body weight or at a dose of between 0.1 mg/kg to about 100 md/kg body weight (page 37 at lines 1-5), while dosage schedules can include once every three days to once every five days, once every week, once every 10 days, once every two weeks, once every three weeks and once a month (e.g., paragraph spanning pages 31-32), although dosage levels may be varied to achieve the desired therapeutic response for a particular patient (page 32 at lines 14-17), and the frequency of multiple sequential doses of an antibody may be administered to a subject over a defined time course (paragraph spanning pages 34-35, page 35-page 36 at line 20). WO2020/163353 A1 teaches that an effective amount is the amount of the antibody which is sufficient to effect treatment of a disease and will vary depending upon the patient and condition being treated (paragraph spanning pages 10-11). Administration may be intravenous (page 34 at lines 14-22) and the patient may be a human (page 35 at lines 20-21, page 12 at lines 15-23). See entire reference including claims.
It would therefore have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used the dosing protocols taught by the art reference and to have treated osteoarthritis as the condition that requires inhibiting opening of Cx43 hemichannels that is an inflammatory disease or disorder as recited in claim 20 of 18/415,511.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, as the claims of 18/415,511 are silent as to the dosing protocol, while the art reference teaches similar antibodies that are used to treat osteoarthritis using those protocols.
The claims of 18/415,511 do not recite wherein an indicator of osteoarthritis severity is assessed at least one day to one week after each does is administered, nor wherein the at least one indicator is improved after the at least one dose (claims 25 and 27).
Tiseo et al. teach administration of an antibody to osteoarthritis patients, wherein pain intensity was recorded daily after administration and subscales for pain, stiffness and function were completed at baseline and at weeks 1, 2, 4, 8, 10, 12, 16, 20 and 25, with all administration at all chosen doses associated with greater improvement in walking knee pain as compared to placebo (see entire reference, including abstract and study assessments section 2.3, and efficacy section 3.2).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have assessed at least one indicator of osteoarthritis severity at least one day to one week after dose administration, and to choose a dose that improves severity.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to assess the effects of administration in real time and to adjust dosages if needed for particular patients.
Instant claims 30-32 are included in this rejection because the light chain and the heavy chain are recited in the alternative, and the light chain of the claims of ‘511 are identical to instantly recited SEQ ID NO: 10.
19. No claim is allowed.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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If attempts to reach the examiner by telephone are unsuccessful, the Examiner’s supervisor, MISOOK YU can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
21. Applicant and the assignee of this application are requested to provide the following information that the Examiner has determined is reasonably necessary to the examination of this application.
CSPC Pharmaceutical Group (12/29/2022, 2 pages) teaches that ALMB-0166 has gained clinical trial approval for treatment of osteoarthritis in humans. The said reference further teaches that ALMB-0166 is a first-in-class humanized monoclonal antibody antagonist for the novel target hemichannel Connexin 43 membrane protein. The reference also teaches that this antibody can significantly relieve joint pain of osteoarthritis (OA) in animals and improve the pathological condition of animal cartilage tissue and can inhibit the release of inflammation and damage promoting factors from osteocytes to protect cartilage tissue and relieve inflammation and pain associated with osteoarthritis (see entire reference).
The admission in the instant specification at [0128] is that the anti-Cx43 antibody used in the working examples in the specification is ALMB-0166 (AlaMab Therapeutices Inc.).
Evidentiary reference AlaMab teaches that ALMB-0166 inactivates connexin43 hemichannels causing them to close (see last paragraph on the second-to-last page).
Neither does the instant specification, nor the art, disclose the sequence of ALMB-0016.
The assumption is that ALMB-0016 is comprised of a subset of the sequences that appear in the instant specification at Table 7.
Please note that neither the Applicant, nor the Inventor of the instant application appear in the said reference, so the said reference could potentially be relevant as prior art.
Applicant is required to provide a concise summary of the relevance of the ALMB-0168 mAb of the reference to the instantly claimed invention in terms of the sequences recited in the instant claims, or to provide evidence that the reference is a disclosure that qualifies as an exception under 102(b)(1).
Note that compliance with the above request cannot reasonably be considered burdensome since the inventor was aware of this reference.
The Applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56.
Failure to comply with this request may be held to be non-responsive.
Also note that any rejection in a subsequent Office Action using the identified reference will not be considered a new ground of rejection.
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