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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 15, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Claim Status
Claims 1-2, 4-6, 10-11, 13-19, and 21-31 are under consideration in this office action.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 against the later invention.
Claims 1-2, 4-6, 10, 13, 17, 19, 24 and 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0016334A1 (“Kehry”; see IDS from 12/22/2021) in view of WO 2020/079086A1 (“Brock”; see PTO-892 from 10/17/22).
Claim 1 is directed to a method of treating myasthenia gravis with a specific anti-FcRn antibody, the method comprising a single loading dose and subsequent maintenance doses.
Kehry teaches an anti-FcRn antibody comprising HCDR 1-3 (SEQ ID NOs: 4-6) and LCDR 1-3 (SEQ ID NOs: 1-3), which are the same HCDRs and LCDRs of the antibody of claim 1 (instant SEQ ID NOs: 6-8 and instant SEQ ID NOs: 3-5, respectively) for the treatment of myasthenia gravis [0142]. The antibody is delivered at a dosage of about 1 mg/kg to about 50 mg/kg [0137], as in instant claim 1. Kehry also teaches a pharmaceutical composition comprising an isolated anti-FcRn antibody and one or more pharmaceutically acceptable carriers or excipients [0047], as in instant claim 19.
Kehry teaches an anti-FcRn antibody comprised of a heavy chain of SEQ ID NO: 24 (instant SEQ ID NO: 2) and a light chain of SEQ ID NO: 19 (instant SEQ ID NO: 1), as in claims 2 and 4. The heavy chain and light chain sequences of Kehry include the variable region heavy chain and variable region light chain of instant SEQ ID NO: 10 and instant SEQ ID NO: 9, respectively, as in claim 5. Kehry also teaches alternate embodiments for the heavy chain and light chain sequences that have a sequence at least 90% identity to the sequence of the heavy chain [0014] and light chain sequence [0013], SEQ ID NO: 24 (instant SEQ ID NO: 2) and SEQ ID NO: 19 (instant SEQ ID NO: 1), respectively. The percent identity (90%) comprises the percent identity recited in claim 2 (95%).
Kehry teaches that the pharmaceutical composition of the anti-FcRn antibody can be delivered intravenously [0072], as in instant claim 6.
Kehry does not explicitly teach an antibody administration protocol comprised of a loading dose and maintenance doses nor does it teach the treatment of patients 18 years and older. Kehry does not teach methods for assessing treatment efficacy of myasthenia gravis.
Brock teaches a method comprising a loading dose/maintenance dose administration protocol for the treatment of myasthenia gravis using an anti-FcRn antibody. This method employs a repeat dose administration strategy with different dosing regimens involving a relatively higher initial dose (i.e. the loading dose) followed by one or more lower doses (maintenance dose). In some embodiments, the maintenance dose is one-quarter or one-half the loading dose (pg 42, ln 22-30). In one embodiment, one or more maintenance dosages are administered at an interval after administration of a loading dose (pg 42, ln 31-33). The patient is 18 years and older (pg 47, ln 21-22), as in claim 24.
The anti-FcRn antibody of Brock reduces serum IgG without any statistically significant decrease in serum albumin concentration (pg 3, ln 16-18), as in instant claim 13.
For claim 17, Brock teaches methods to assess changes from baseline using several metrics for characterizing myasthenia gravis and treatment efficacy (pg 36, ln 9-10). These include MG-ADL score (pg 34, ln 38), QMG score (pg 34, ln 37), MG-Qol-15r score (pg 36, ln 27-28), and clinical classification tool MGFA score (pg 33, ln 24-26). These metrics provide a consistent methodology for assessing clinical response and include-patient centered outcomes (pg 34, ln 38-40).
In view of the combined teachings of the references, one of ordinary skill in the art would have understood that the anti-FcRn antibody of Kehry was an alternate therapeutic for myasthenia gravis to the anti-FcRn antibody of Brock. As is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)." Accordingly, absent convincing evidence to the contrary, it would have been obvious to the ordinary artisan prior to the effective filing date of the claimed invention to apply a loading dose/maintenance dose protocol of Brock to the antibody taught by Kehry. Given the teachings of the combination of references, one of ordinary skill in the art would have reasonably expected to have identified the doses in the range of Kehry, using and modifying the loading/maintenance dose administration protocol of Brock to generate the preferred/optimized therapeutic dosing protocol of the instant claims through routine optimization of the protocol (see MPEP § 2144.05). This is because the artisan has good reason to pursue known options within their technical grasp to obtain predictable results. Such would amount to the combining of prior art element according to known methods to achieve predictable results.
Claims 13-18, 21-23, and 29-31 are directed to expected results in a method of treating a patient with myasthenia gravis with an anti-FcRn antibody of HCDR1-3 of SEQ ID NOs: 6-8 and LCDR1-3 of SEQ ID NOs: 3-5. Kehry in view of Brock teaches the antibody and dosing regimen. Therefore, it would be expected that the method of treating taught by Kehry in view Brock would reduce serum albumin (claim 13), reduce autoantibodies (claim 14-16), change MG-ADL score, QMG score, MG-ZoL-15r score, or MGFA score (claim 17, 29-31), not change HDL, LDL, or triglycerides (claim 18),and reduce IgG, because the antibody of Kehry is the same as the instant claims. The results of claims 13-18, 21-23, and 29-31 would have been predicted because the antibody and dosing regimen of Kehry in view of Brock satisfies all limitations set forth in the claims, and it necessarily follows that the antibody inherently possesses the functionality and the ability to serve the expected results recited in the claims, absent objective evidence to the contrary.
Given that both Kehry and Brock are drawn to anti-FcRn monoclonal antibody treatment for myasthenia gravis and further given that Brock discloses reliable methods to monitor progression of myasthenia gravis based on these tests, it would have been obvious to one of ordinary skill in the art to use the metrics of evaluation taught by Brock in the assessment of the antibody of Kehry because improvement in these parameters reflect an improvement in myasthenia gravis. One would use these metrics and have reasonable expect of successfully monitor disease progression, absent evidence to the contrary.
Claims 1-2, 4-6, 10-11, 13, 17, 19, 21-24 and 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Kehry in view of Brock as applied to claims 1-2, 4-6, 10, 13, 17, 19, 24, and 29-31 above, and further in view of Ling et al (“Ling”; see PTO-892 from 10/17/22).
The combined disclosures of Kehry and Brock teach administration of a loading dose and maintenance doses for the anti-FcRn antibody treatment of myasthenia gravis. Kehry also teaches that the anti-FcRn antibody is useful to promote catabolism and clearance of IgG and IgG autoantibodies to reduce the immune response [0140]. These references do not teach infusion time for the anti-FcRn antibody nor do they teach anti-FcRn mediated percent decrease of specific IgG subtypes.
Ling teaches a study in healthy volunteers for the assessment of the pharmacodynamics, pharmacokinetics, and safety of the anti-FcRn antibody M281 (the same antibody of the instant claims) (Abstract). Ling teaches the administration of M281 as an intravenous infusion over 2 hours (pg 1037, column 2, paragraph 3, ln 9-13), as in claim 11.
Ling also teaches that anti-FcRn treatment reduces serum IgG (or any subtype or combination thereof). As shown in Figure 3 of Ling, serum IgG levels decrease within 7-14 days to 75-90% below baseline levels; this effect is specific for IgG, as no change was observed for IgM, IgA, or IgE (pg 1033, Column 2, ln 18-20), as in claims 21-23.
The combined references teach the instant method comprising infusion of an antibody over a given time and the assessment of reduction in specific immunoglobulin species following anti-FcRn treatment. As Ling teaches use of the same antibody as the instant claims, it follows that using the same product in the loading dose/maintenance dose protocol taught by the combined disclosures of Kehry and Brock would expectedly be associated with a decrease in IgG.
Claims 1-2, 4-6, 10-11, 13-17, 19, and 21-31 are rejected under 35 U.S.C. 103 as being unpatentable over Kehry in view of Brock and Ling, as applied to claims 1-2, 4-6, 10-11, 13, 17, 19, 21-24, and 29-31 above, and further in view of Lazaridis et al (“Lazaridis”; PTO-892 from 10/17/22).
Brock teaches that myasthenia gravis is an autoimmune disease caused by autoantibodies targeting neuromuscular junction proteins. In the majority of patients, antibodies against the muscle AChR are detected, while in 6% of patients, antibodies against MuSK are detected. Reduction in the serum levels of anti-MuSK antibody and/or AChR antibody is a metric of treatment efficacy (pg 37, ln 9-10). Dosing with the anti-FcRn antibody of Brock decreases AChR antibody levels by approximately 65% at 4 weeks after initiation of weekly treatment (see Figure 4). The disclosures of Kehry, Brock, and Ling do not teach the detection of autoantibodies besides anti-MuSK and anti-AchR antibodies in myasthenia gravis patients.
Lazaridis teaches the detection of autoantibodies for LRP4, titin, the ryanodine receptor, agrin, collagen Q, Kv1.4 potassium channels, and cortactin, which can be useful biomarkers for myasthenia gravis (see abstract), as in claim 14. Therefore, it would have been obvious to one of ordinary skill in the art to use the autoantibodies of Lazaridis to assess the efficacy of the anti-FcRn antibody of Kehry in myasthenia gravis because change in autoantibody level is a reliable metric of myasthenia gravis severity. Since not all patients with myasthenia gravis exhibit changes in AChR or MuSK autoantibodies, these additional autoantibodies are important for assessing a more inclusive group of patients with myasthenia gravis (e.g., those patients who are not positive for autoantibodies for AChR or MuSK).
Claim 1-2, 4-6, 10-11, 13-19, and 21-31 are rejected under 35 U.S.C. 103 as being unpatentable over Kehry in view of Brock, Ling, and Lazaridis as applied to claims 1-2, 4-6, 10-11, 13-17, 19, 21-31 above, and further in view of Roopenian et al (“Roopenian”; PTO-892 from 10/17/22).
The teachings of Kehry, Brock, Ling and Lazaridis are discussed above. These combined references do not teach that treatment with anti-FcRn antibody does not significantly increase levels of cholesterol, HDL, LDL, and triglycerides.
Roopenian teaches that one of the many physiological functions of serum albumin is the transport of cholesterol, steroids, fatty acids, various minerals, etc. (pg 344, column 1, ln 12-15). When levels of serum albumin are reduced, total cholesterol, LDL, and triglycerides are increased. This relationship was studied in albumin-deficient mice by Roopenian, who teaches that albumin null mice show elevated levels of cholesterol, LDL, HDL, and triglycerides (pg 345, column 2, ln 35-44). Given the role of FcRn in preventing the catabolism of albumin (abstract), and further given that decreased albumin levels are linked to hypercholesterolemia, it would have been obvious to one of ordinary skill in the art that a useful anti-FcRn treatment for myasthenia gravis would be one that does not significantly increase levels of cholesterol or significantly decrease the level of serum albumin because this outcome is adverse.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4-6, 10-11, 13-19, and 21-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5-28 of copending Application No. 18/286,455. Although the claims at issue are not identical, they are not patentably distinct from each other because are both directed to a method of treating myasthenia gravis using the same anti-FcRn antibody with the same dosing administration protocol.
The claims of ‘455 are directed to a method of treating pediatric myasthenia gravis by administering an anti-FcRn antibody of heavy chain comprising HCDR1-3 of SEQ ID NOs: 6-8 and light chain comprising LCDR1-3 comprising LCDR1-3 of SEQ ID NOs: 3-5 at a loading dose of about 30 mg/kg to about 60 mg/kg followed by a maintenance dose of about 15 mg/kg to about 30 mg/kg. The anti-FcRn antibody is identical to the antibody of instant claim 1 (same SEQ ID NOs), and the claimed dosages fall within the range of ‘455.
‘455 teaches a method for treating patients with pediatric myasthenia gravis with the claimed anti-FcRn antibody. As the instant claims are directed to a method of treating the genus myasthenia gravis, the scope of the disease treated by ‘455 is narrower than the disease treated by the instant claims, and the method of ‘455 is a species of the genus recited in the instant claims. “"A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus,” In re Slayter, 276 F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960); In re Gosteli, 872 F.2d 1008, 10 USPQ2d 1614 (Fed. Cir. 1989), see MPEP 2131.02. Therefore, the method of treating myasthenia gravis of the instant claims are anticipated over the method of treating pediatric myasthenia gravis copending application ‘455.
The scope of the instant claims are fully encompassed in the reference claims, and it would have been obvious to one of ordinary skill in the art that the method and antibody of ‘455 are the same as those of the instant claims. Therefore, the claims of the two applications 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.
Claims 1-2, 4-6, 10-11, 13-19, and 21-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 89-91 and 93-99, 102 of copending Application No. 17/597,928 in view of Brock. Although the claims at issue are not identical, they are not patentably distinct from each other because they are both directed to use of a specific anti-FcRn antibody for the treatment of myasthenia gravis. The antibody of instant claims 1 and 19 is comprised of HCDR1-3 of SEQ ID NOs: 6, 7, and 8 and LCDR1-3 of SEQ ID NOs: 3, 4, and 5 is identical to that of the copending antibody of claims 89-90 comprised of HCDR1-3 of SEQ ID NOs: 4, 8, and 11 and LCDR1-3 of SEQ ID NOs 1, 2, and 3. The heavy chain and light chain amino acid pair of SEQ ID NO: 2 and SEQ ID NO: 1, respectively, of instant claims 2 and 4 are identical to the heavy chain and light chain amino acid pair of SEQ ID NO: 24 and SEQ ID NO: 19 of ‘958 claim 97. The heavy chain and light chain amino acid pair of SEQ ID NO: 24 and SEQ ID NO: 19 of ‘958 are comprised of the same variable region heavy chain and variable region light chain pair of SEQ ID NO: 10 and SEQ ID NO: 9, respectively, of instant claim 5.
Although the copending application discloses the anti-FcRn antibody, it does not provide for the limitation of a loading/maintenance dose administration protocol nor does it provide for the limitations of a reduction in serum IgG, albumin, anti-AChR antibodies, and anti-MuSK antibodies in the patient, achieving change in baseline MG-ADL score, QMG score, MG-Qol-15r score, or MGFA score in the patient, or not significantly increasing levels of total cholesterol, HDL, calculated LDL, or triglycerides.
Brock teaches a method comprising a loading dose/maintenance dose administration protocol for the treatment of myasthenia gravis using an anti-FcRn antibody. This method employs a repeat dose administration strategy with different dosing regimens involving a relatively higher initial dose (i.e. the loading dose) followed by one or more lower doses (maintenance dose). In some embodiments, the maintenance dose is one-quarter or one-half the loading dose (pg 42, ln 22-30). In one embodiment, one or more maintenance dosages are administered at an interval after administration of a loading dose (pg 42, ln 31-33), which is consistent with the use of a single loading dose, as in instant claim 1.
In view of the combined teachings of the references, one of ordinary skill in the art would have understood that the anti-FcRn antibody of ‘928 was an alternate equivalent therapeutic for myasthenia gravis to the anti-FcRn antibody of Brock. Accordingly, it would have been obvious to the ordinary artisan prior to the effective filing date of the claimed invention to apply a loading dose/maintenance dose protocol of Brock to the antibody of ‘928, as instant claims 1, 10-11, and 19. Overall, given the teachings of the combination of references, one of ordinary skill in the art would have reasonably expected to have identified the doses in the range of ‘928, using the loading/maintenance dose administration protocol of Brock to optimize the therapeutic dosing protocol.
While ‘958 and Brock are silent regarding reducing serum IgG, albumin, anti-AChR antibodies, or anti-MuSK antibodies in the patient, achieving as in instant claims 13-16 and 21-22, achieving change in baseline MG-ADL score, QMG score, MG-Qol-15r score, or MGFA score in the patient, as in instant claim 17, or not significantly increasing levels of total cholesterol, HDL, calculated LDL, or triglycerides, as in instant claim 19, it is clear that the same antibody directed against FCRN would have the same characteristics as the instantly claimed composition since there is no evidence to the contrary. Note that rejections for obviousness are appropriate when the prior art discloses a method (or product) that appears to be identical except that the art is silent as to an inherent property; see MPEP § 2112(III). In such situations, the burden is on applicant to provide evidence that the prior art product (or method) is not an obvious variant; see MPEP § 2112(V).
The scope of the instant claims are fully encompassed in the reference claims, and it would have been obvious to one of ordinary skill in the art that the method and antibody of ‘928 are the same as those of the instant claims. Therefore, the claims of the two applications 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.
Response to Amendment
The affidavit under 37 CFR 1.132 filed on November 10, 2025 (“Sheehan Declaration”) is insufficient to overcome the rejection of claims 1-2, 4-6, 10, 13, 17, 19, 24 and 29-31 based upon the combined teachings of Kehry and Brock under 35 U.S.C. 103 as set forth in the last Office; reasons are provided below in the response to arguments.
Response to Arguments
Applicant's arguments filed September 23, 2024 have been fully considered but they are not persuasive.
Applicant asserts that Kehry in view of Brock does not teach or suggest selection of the claimed dosing regimen because a person of skill in the art not would not have had a reasonable expectation of success in identifying a therapeutically effective dose based on Kehry in view of Brock (remarks, pg 7). Applicant references recent Federal Circuit opinion Janssen Pharmaceuticals, Inc. v. Teva Pharmaceuticals USA, Inc., 141 F.4th 1367, 1378 (C.A. Fed (N.J.), 2025) (“Janssen”). In this decision, the Court found that a combination of doses (i.e. a loading dose/maintenance dose protocol) was not obvious over cited art that taught a range that encompasses the claimed doses (remarks, pg 9). The crucial choice made by Janssen was the choice to start with a particular high first loading dose and then follow it with a second, lower loading dose. After review of Janssen, the examiner finds that the specific facts and procedural posture of Janssen do not apply to the instant claims. The main disparity is that the two agents under consideration in Janssen, paliperidone and haloperidol, were not found to be equivalents (structurally or functionally), and thus the motivation to use a loading/maintenance dose of haloperidol in a dosing regimen for paliperidone was not obvious. In the instant case, however, the agents are two anti-FcRn antibodies that block FcRn and are equivalents. Because Kehry teaches the antibody and dose and Brock teaches the loading/maintenance dose protocol of an anti-FcRn antibody, the claimed dosing regimen is obvious. The criticality of choosing a loading a choice is obvious, because Brock teaches the utility of loading doses for anti-FcRn antibodies in treating autoimmune disease.
Applicant asserts that there is uncertainty is selecting a therapeutically effective dose and that this uncertainty is only magnified when the process is moved from animal models to human patients (remarks, pg 10). Applicant is directed to Tosi et al (PTO-892 from 1/15/2025), which is an evidentiary reference for response to arguments and not cited as a new reference in the rejection. Tosi et al teaches approaches for the development of starting doses for first-in-human trials of monoclonal antibodies (abstract; pg 2159, column 1, para 1). Preclinical evidence that provided guidance for the choice of starting dose was primarily in non-human primates and rodents (pg 2159, column 2, “SD Selection and Administration Schedule”). Although Kehry does demonstrate effects of the antibody in mice, this does not limit the applicability of the method to mice only. Indeed, Kehry teaches that the anti-FcRn antibodies may be used in a method of treating an autoimmune disease in a subject [0123], including humans [0071]. Because Kehry teaches the antibody and dose and Brock teaches the loading/maintenance dosing regimen, it would have been obvious to one of ordinary skill in the art to modify the dose and dose interval of Kehry to reach the claimed dose and interval via routine optimization.
Routine optimization is comprised of methods that are well-understood and conventional activities previously known to the industry. When considering whether the determination of the optimum or workable ranges of a variable (e.g. dose or dose interval) might be characterized as routine experimentation, the particular parameter must first be recognized as a result-effective variable (see MPEP 2144.05(I)-(II). KSR International Co. v. Teleflex held that “obvious to try” was a valid rational for an obviousness finding when the invention is directed to a result-effective variable. In this case, an artisan prior to the effective filing date of the invention would have a reason to vary the dose and dose interval of the anti-FnRn antibody of Kehry (using general guidance from Brock) because both were recognized as result-effective variables in the field of antibody therapy. One of ordinary skill in the art would have a reasonable and predictable expectation of arriving at the claimed dosing regimen.
Applicant argues that there is no presumption of enablement and operability because the cited references fail to teach all the claim limitations and because there is no reasonable expectation of success in selecting the therapeutic dose (remarks, pg 10-11). According to the Sheehan Declaration, it is challenging to arrive at a dosing regimen that is both safe and effective, because the nipocalimab (the claimed antibody) not only targets pathogenic autoantibodies for clearance but also the therapeutic antibody itself (remarks, pg 13). Sheehan Declaration also emphasizes that the claimed dosing regimen was selected based on observed data from Phase 2 study and PK/PD/efficacy modeling analyses and that there is no reason to believe that the claimed dosing regimen could have been arrived at by blindly selecting a dosing schedule from Kehry and Brock (remarks, pg 14). The examiner agrees that the dose could not have been arrived at blindly; however, the dose was arrived by routine optimization, via methods well-known to those of ordinary skill in the antibody therapy art (e.g. PK/PD/efficacy modeling analyses). The identification of a dose within the broad range of Kehry could have been achieved through routine optimization because the concentration of antibody is a result effective variable, which can be routinely determined and optimized in the pharmaceutical arts. The determination of the exact doses in view of the patient’s conditions is well within the skill of those skilled artisans. Further, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215,219 (CCPA 1980). It would be conventional and within the skill of the art to identify and determine the optimum dose and timing of administration protocols to treat myasthenia gravis. When other methods similar to a claimed method have been successful, the court has determined there would have been a reasonable expectation of success. For example, in Velander v. Garner, 348 F.3d 1359, 1379 (Fed. Cir. 2003), a reasonable expectation of success was found for a method of producing a particular protein when several other proteins had been produced in a similar way. The doses within the antibody Kehry in view of Brock are not dissimilar in kind and the results identified by applicant are not unexpectedly good; the examiner finds that the claimed dose was determined by routine methods using method known in the art.
When provided with all of the starting conditions, including the antibody, dose, and disease of Kehry and the loading/maintenance dose protocol for an anti-FcRn antibody of Brock, discovering the optimum or workable ranges for those components when performing the prior art method of treatment by routine experimentation does not make the instant claims patentable. That which is claimed is merely the optimization of variables within the claims that flow from the “normal desire of scientists or artisans to improve upon what is already generally known.” In re Peterson, 315 F.3d 1325,
1330 (Fed.Cir.2003).
Arguments related to the challenges of determining a dose (remarks, pg 16) are not persuasive, because Kehry teaches the dose range. The examiner maintain their position that identification of the dose within the range of Kehry is obvious. Applicant has provided evidence (Tang et al) demonstrating that developing new therapeutic doses is challenging and that selection of a dose and a dosing regimen are highly uncertain (remarks, pg 17). The complexity of determining an optimal dose of a monoclonal antibody is appreciated by the examiner. However, achievement of this goal is possible via method known in the art, especially since dose and dose interval are result-effective variables. Increasing the dose of the anti-FcRn antibody increases response (figure 4 of Kehry), demonstrating that dose amount is recognized in the art as result-effective variable. In the instant case, Kehry teaches the antibody and the doses, and Brock teaches a different anti-FcRn antibody and a loading/maintenance dose protocol. One looking to treat myasthenia gravis with the anti-FcRn antibody of Kehry would look to the method of Brock, as use of an anti-FcRn antibody in a loading/maintenance dose protocol had already been expressly contemplated. One would use the antibody of Kehry in this method and have a reasonable expectation of success, especially since Kehry teaches a dose range that includes the claimed dose.
Without evidence of unexpected results or a teaching away in the prior art, the claimed dosages of Kehry in the loading/maintenance dose protocol of Brock would have been obvious to one of ordinary skill in the art. One would modify the teachings of Kehry and Brock by varying the dose protocol to arrive at the presently claimed method to treat myasthenia gravis, especially since the prior art already recognized that dose modification is part of routine optimization; this includes dose, dose interval, and number of doses. A person of ordinary skill in the art would have been motivated to apply a dose within the dose range Kehry in the method of Brock and have reasonably expected success for the effective treatment of myasthenia gravis.
Dr Sheehan states that one of ordinary skill in the art would not have expected to achieve the sustained reduction in total IgG and anti-AchR antutoantibody serum concentrations that the claimed therapy provides when compared to other known anti-FcRn therapies (remarks, pg 22). In the figure on pg 22 of remarks, the efficacy of two anti-FcRn antibodies, nipocalimab and rozanolixizumab, to decrease serum IgG and anti-AchR antibody are compared. The dosing regimen for these two antibodies are not the same, with nipocalimab delivered every two weeks and rozanolixizumab delivered once a week for only 6 weeks (remarks, pg 22). The prolonged efficacy of nipocalimab is not unexpected, as the therapeutic is delivered for the entire timeline.
Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007). The rejections under 35 U.S.C. 103 are maintained.
Regarding the provisional rejection of the claims as being unpatentable over copending U.S. Application No. 18/268,455, applicant argues that because ‘455 has a later patent term filing date than the instant application, this rejection is improper. According to MPEP 822.01, a ‘provisional” double patenting rejection should continue to be made by the examiner in each application as long as there are conflicting claims in more than one application unless that “provisional” double patenting rejection is the only rejection remaining in one of the applications. As the rejection under 35 U.S.C. 103 is maintained, this rejection is not improper.
Regarding the provisional nonstatutory double rejection over copending application 17/597,928 in view of Brock, applicant is directed to the arguments above with respect to the rejections under 35 U.S.C. 103 (see pg 12-17).
Conclusion
No claim is allowed.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675