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 .
Priority
This application is a Continuation of 19/016,557 filed 01/10/2025 which is a Continuation of 18/671,648 filed on 05/22/2024 now abandoned, which is a Continuation of 18/486,083 filed on10/12/2023 now abandoned which is a Continuation of 18/162,571 filed on 01/31/2023 now abandoned which is a Continuation of 17/096,637 filed on 11/12/2020 now abandoned which is a Continuation of 16/882,206 filed on 05/22/2020 now U.S. Patent No. 10864197 which is a Continuation of 16/340,848 filed on 04/10/2019 now abandoned which is a national stage entry of PCT/US2017/056538 filed on 10/13/2017 which claims priority to U.S. Provisional Application No. 62/423,079 filed on 11/16/2016 and U.S. Provisional Application No. 62/407,860 filed on 10/13/2016.
Response to Amendment
No amendments to the claims were made by Applicant’s reply filed on December 5, 2025. Claims 1-44 are canceled. Claims 45-72 are currently pending.
Response to Arguments
The terminal disclaimer filed on December 5, 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on U.S. Application No. 19/253,088 has been reviewed and is accepted. The terminal disclaimer has been recorded.
The terminal disclaimer filed on December 5, 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 10,864,197 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Accordingly, the previous double patenting rejections over U.S. Application No. 19/253,088 and U.S. Patent No. 10,864,197 are hereby withdrawn.
Due to the abandonment of copending Application No. 19/016,557, the previous double patenting rejection over U.S. Application No. 19/016,557 is hereby withdrawn.
Applicant's arguments filed December 5, 2025 with respect to the remaining rejections have been fully considered but they are not persuasive.
With respect to the rejection of claims 45-72 under 35 U.S.C. 103 as being unpatentable over Retrophin, Applicant argues that the mere presence of Applicant's claimed dosages in the prior art cannot serve as the basis for a finding of prima facie obviousness based on routine optimization absent more. Applicant further argues in a recent court decision In Janssen Pharms., Inc. v. Teva Pharms., the Federal Circuit recently held that Janssen's paliperidone palmitate dosing regimen comprising first (150 mg-eq.) and second (100 mg-eq.) loading doses was not obvious even though a published clinical trial protocol disclosed administration of at least three equal doses of 50, 100, or 150 mg- eq. of paliperidone palmitate at specified time intervals, and another reference disclosed a range containing 100 mg-eq. and 150 mg-eq paliperidone palmitate.
These arguments are found not persuasive because generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
Applicant can rebut a prima facie case of obviousness by showing the criticality of the range. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See also Minerals Separation, Ltd. v. Hyde, 242 U.S. 261, 271 (1916) (a patent based on a change in the proportions of a prior product or process (changing from 4-10% oil to 1% oil) must be confined to the proportions that were shown to be critical (1%)); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205 (CCPA 1946) ("Where the issue of criticality is involved, the applicant has the burden of establishing his position by a proper showing of the facts upon which he relies."); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Lilienfeld, 67 F.2d 920, 924 (CCPA 1933) ("It is well established that, while a change in the proportions of a combination shown to be old, such as is here involved, may be inventive, such changes must be critical as compared with the proportions used in the prior processes, producing a difference in kind rather than degree."); In re Wells, 56 F.2d 674, 675, 12 USPQ 430 (CCPA 1932) ("Changes in proportions of agents used in combinations . . . in order to be patentable, must be critical as compared with the proportions of the prior processes."); E.I. DuPont de Nemours & Company v. Synvina C.V., 904 F.3d 996, 1006, 128 USPQ2d 1193, 1201 (Fed. Cir. 2018.)("[A] modification of a process parameter may be patentable if it ‘produce[s] a new and unexpected result which is different in kind and not merely in degree from the results of the prior art." (citing Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023) ("A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘a new property dissimilar to the known property,’ rather than producing a predictable result but to an unexpected extent.").
In the instant case, Applicant has not provided any unexpected or surprising results as compared to the prior art with respect to their specific treatment regimen. Furthermore, as opposed to the Janssen case cited by Applicant, the claims of the instant application recite starting with a low dosage and increasing the dosage after a period of time. It is noted that the claims of the instant application are drawn to the treatment of patients having a UP/C ratio of greater than 1.5 g/g and thus patients having kidney disease. Retrophin teaches that RE-021 (Sparsentan) will be administered as a single oral morning dose in an amount of 400mg, and patients ≤50 kg will receive half of that dose which is 200 mg once per day (Arms/intervention). Retrophin further teaches that RE-021 (Sparsentan) will be administered as a single oral morning dose in an amount of 800 mg, and patients ≤50 kg will receive half of that dose which is 400 mg (Arms/intervention). Since the patient has kidney disease, it would have been obvious and within the skill of an ordinary artisan to use caution in treatment and start the patient with the lowest dose which is 200 mg for patients ≤50 kg as taught by Retrophin or 400 mg for patients >50 kg and increase the dosage as needed to prevent any adverse effects. Thus, it would not be unreasonable to start the dosing low and increase the dose overtime with caution to prevent adverse effects which is contrary to the Janssen case which is directed to starting with a high dosage of an antipsychotic drug and reducing the dosage. Thus the rejected claims do not fall into the paradigm established by the Janssen case argued by Applicant. Furthermore, the Janssen case cited by Applicant is not precedential and thus does not serve as authority when considering other similar cases.
Applicant further argues that although the Office alleges that "Retrophin also teaches the secondary efficacy endpoint is the proportion of FSGS patients experiencing a UP/C ratio <1.5 g/g and >40% reduction from baseline in UP/C at Week 8 over a range of dose levels compared to treatment with irbesartan as active control (secondary outcome measures)," the version of Retrophin available on clinicaltrials.gov as of this application's priority date does not disclose the presently recited secondary endpoint and only provides a single primary endpoint. Applicant argues that although the clinical trial protocol for NCT01613118 was updated in April 2025 to include the secondary endpoint discussed in the Office Action, the secondary endpoint referenced by the Office was not available as prior art in view of the present application's priority date and cannot be relied upon by the Office. Thus Applicant argues that nothing in Retrophin provides a reasonable expectation that the claimed dosing regimen reduces the subject's UP/C ratio by 40% or more relative to the subject's baseline UP/C ratio (greater than 1.5 g/g).
These arguments are found not persuasive because even if the secondary endpoint was not available before the effective filing date of the claimed invention, said results as claimed are rendered obvious since the method of claims 45, 67 and 70 are rendered obvious and thus the effects achieved by the methods as claimed are also rendered obvious. Thus reducing the subject’s UP/C ratio by 40% or more relative to baseline as claimed in the time frame as claimed and reducing the subject’s UP/C ratio by 20% or more as claimed as compared to treatment with irbesartan as claimed are rendered obvious since the method rendered obvious over the prior art teachings will necessarily produce the same results and effects as claimed. Thus administration of the same amount of the same compound for the treatment of the same disorder will necessarily have the same effects as claimed. Thus in the absence of a demonstration that the specific treatment regimen is critical to achieve the effects as claimed, the cited claims of the instant application are rendered obvious over the cited prior art teachings.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
With respect to the rejection of claims 45-72 under 35 U.S.C. 103 over Zhang et al. in view of Montane et al. and Komers et al., the declaration under 37 CFR 1.130(a) filed on December 4, 2025 is sufficient to remove the Komers et al. (Am J Physiol Regul Integr Comp Physiol 310: R877–R884, 2016. First published March 23, 2016) reference as prior art based on the 102(b)(1) exception as being disclosed by inventor or obtained from inventor.
However, the removal of the Komers reference is not sufficient to overcome the rejection under 35 USC 103 over the remaining references. Komers et al. was included as a secondary reference to provide evidence that the method rendered obvious over the teachings of Zhang et al. will necessarily result in decreases in proteinuria. Since Zhang et al. teaches administration of the same compound as claimed, the same results or effects which is reducing proteinuria will necessarily occur. Thus decreasing proteinuria is an inherent effect of the administration of the claimed compound. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In addition, it is not necessary that the prior art suggests the same advantage or result discovered by applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991). The mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Prindle, 297 F.2d 251, 254 (CCPA 1962). Here, the latent property identified by Applicant is reducing proteinuria which will necessarily occur by following the teachings and suggestions of the prior art and administering the claimed compound to a subject with FSGS.
In addition, the teachings of Komers were not necessary in the rejection of record but merely added to further substantiate the teachings of Montane et al. which teaches that the addition of angiotensin blockage treatment results in a decrease in proteinuria. Thus, Montane et al. suggests without the teachings of Komers that the method of Zhang et al. which administers an inhibitor of angiotensin II would have necessarily resulted in the decreases in proteinuria as claimed since the teachings of Montaine et al. which comprise the inhibition of angiotensin II resulted in decreases in proteinuria. Thus removing the Komers reference from the rejection does not change the rejection and is not a new grounds of rejection.
Applicant's arguments filed December 5, 2025 with respect to the remaining references have been fully considered but they are not persuasive. Applicant argues that Zhang discloses, among other things, methods of treating certain nephrotic disorders using specified amounts of sparsentan, (e.g. 200 mg, 400 mg, and 800 mg). But just like Retrophin, and for substantially the reasons outlined by the Federal Circuit in Janssen, supra, the mere fact Zhang discloses certain amounts of sparsentan is insufficient to provide a rationale for adopting the presently claimed dosing regimen absent significantly more, none of which is present in Zhang.
These arguments are found not persuasive for the same reasons as detailed above. In addition, Zhang et al. teaches the treatment of glomerulosclerosis with sparsentan with a minimal dosage of 200 mg/day (claims 36-40). Since the patient has kidney disease, it would have been obvious and within the skill of an ordinary artisan to start the patient with the lowest dose which is 200 mg as taught by Zhang et al. and increase the dosage as needed to prevent any adverse effects. Thus, it would not be unreasonable to start the dosing low and increase the dose overtime with caution to prevent adverse effects which is contrary to the Janssen case which is directed to starting with a high dosage of an antipsychotic drug and reducing the dosage. Thus as detailed above, the rejected claims do not fall into the paradigm established by the Jansen case argued by Applicant. Furthermore, this case cited by Applicant is not precedential and thus does not serve as authority when considering other similar cases. Therefore, as detailed above, in the absence of a demonstration that the claimed treatment regimen is critical to achieve the effects as claimed, the claims of the instant application are rendered obvious in view of the cited prior art teachings.
Applicant’s arguments with respect to the Montane reference are found not persuasive since Montane is a secondary reference provided in the rejection to cure the deficiency of Zhang which does not specifically teach treating a subject having a baseline UP/C ratio of 1.5 g/g or more. Applicant’s argument that Montane teaches away from using a baseline UP/C ratio of 1.5 since Montane teaches a baseline of 2.0 g/g is found not persuasive since the claims of the instant application recite “wherein the subject has a baseline UP/C ratio of 1.5 g/g or more.” Thus Montane’s teaching of greater than 2.0 g/g meets the claimed limitation of 1.5 g/g or more.
Applicant further argues that Montane teaches a combination of compounds which include angiotensin blockade and does not specifically teach that the decrease in proteinuria is directly from the angiotensin blockade. These arguments are found not persuasive since Montane et al. teaches that subjects with the type of focal segmental glomerulosclerosis (FSGS) benefit from angiotensin blockade for the treatment of glomerulosclerosis wherein patients with FSGS present with nephrotic-range proteinuria which exceeds a UP/C >2.0 mg/mg, while normal proteinuria is considered ≤0.2–0.6. Thus based on the teachings of Zhang et al., one would have been motivated to choose any patient with glomerulosclerosis in need of treatment including those having FSGS with increased levels of proteinuria as measured by UP/C with nephrotic-range proteinuria that exceeds a UP/C >2.0 mg/mg. Moreover, Montane et al. specifically teaches that treatment which comprises angiotensin blockade reduces proteinuria and thus one would reasonably expect angiotensin blockade to contribute to the reduction in proteinuria. Since sparsentan is an angiotensin blocker as taught by Zhang et al., an ordinary skilled artisan would have reasonably expected that the method of Zhang et al. which administers an angiotensin blocker would also result in reduction in proteinuria and decreases in UP/C ratio relative to the subject’s baseline UP/C ratio.
Thus based on the teachings of Zhang et al., one would have been motivated to choose any patient with glomerulosclerosis for treatment with sparsentan, but especially those having an increased risk of kidney injury including those having a baseline UPCR of greater than 1.5 g/g as claimed and thus having increased levels of proteinuria as taught by Montane et al. Furthermore, even without the teachings of Montane pertaining to proteinuria reduction, the cited prior art renders obvious the methods of claims 45, 67 and 70 and treating a subject with FSGS having a baseline UP/C ratio of greater than 1.5 g/g comprising the administration of effective amounts of sparsentan and thus the effects achieved by the methods as claimed are also rendered obvious. Thus reducing proteinuria and the subject’s UP/C ratio by 40% or more as claimed relative to baseline, in the time frame as claimed are rendered obvious since the method rendered obvious over the prior art teachings will necessarily produce the same results and effects as claimed.
The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In addition, it is not necessary that the prior art suggests the same advantage or result discovered by applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991). The mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Prindle, 297 F.2d 251, 254 (CCPA 1962). Here, the latent property identified by Applicant is that sparsentan decreases proteinuria and reduces UP/C ratio in patients with FSGS, which will necessarily occur in the prior art by following the teachings and suggestions of the prior art and administering an effective amount of sparsentan for the treatment of FSGS. Thus as detailed above, in the absence of a demonstration that the claimed treatment regimen is critical to achieve the effects as claimed, the claims of the instant application are rendered obvious in view of the cited prior art teachings.
Accordingly, the previous rejections under 35 USC 103 are hereby maintained and reproduced below without the Komers reference. This action is final.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 45-72 are rejected under 35 U.S.C. 103 as being unpatentable over Retrophin, Inc., "Randomized, Double-Blind, Safety and Efficacy Study of RE-021 (Sparsentan) in Focal Segmental Glomerulosclerosis (DUET)," ClinicalTrials.gov, ClinicalTrials.gov Identifier; NCT01613118, 2012 (Provided on IDS) herein referred to as Retrophin.
Claims 45-72 of the instant application claim a method of treating a subject with focal segmental glomerulosclerosis (FSGS) comprising (a) for a subject weighing less than or equal to 50 kg, (i) orally administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; (ii) after the initial 14-day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day; or (b) for a subject weighing more than 50 kg, (i) orally administering an initial dose of 400 mg of sparsentan to the subject once a day for a period of 14 days; (ii) after the initial 14-day period, orally administering a subsequent dose of 800 mg of sparsentan to the subject once a day, wherein the subject has a baseline UP/C ratio of 1.5 g/g or more, and wherein the subject’s urine protein to creatinine (UP/C) ratio is reduced by 40% or more relative to the subject’s baseline UP/C ratio.
Retrophin teaches RE-021 (Sparsentan), a selective dual-acting receptor antagonist with affinity for endothelin (A type) and angiotensin II receptors (Type 1) for treating patients with focal segmental glomerulosclerosis (FSGS) (Brief Summary). Retrophin teaches that focal segmental glomerulosclerosis (FSGS) is a rare glomerular disorder which results in frank proteinuria and in some patients progression to end-stage kidney disease (ESKD) over 5-10 years, wherein proteinuria reduction is widely regarded to be beneficial and is considered the primary goal of treatment in FSGS and slowing its progressive course (Detailed description).
Retrophin teaches treating patients with FSGS with a urine protein/creatinine ratio (UP/C) at or above 1.0 g/g ages 8 years to 75 years old (eligibility criteria). Retrophin teaches that RE-021 (Sparsentan) will be administered as a single oral morning dose in an amount of 400mg, and patients ≤50 kg will receive half of that dose which is 200 mg once per day (Arms/intervention). Retrophin further teaches that RE-021 (Sparsentan) will be administered as a single oral morning dose in an amount of 800 mg, and patients ≤50 kg will receive half of that dose which is 400 mg (Arms/intervention). Retrophin further teaches that some patients will be administered 300 mg of irbesartan for purposes of comparison with sparsentan treatment (Arms/intervention).
Retrophin further teaches that the primary efficacy objective is to determine the change in UP/C in FSGS patients receiving RE-021 (Sparsentan) from baseline to 8 weeks over a range of dose levels compared to treatment with irbesartan as active control (primary outcome measures). Retrophin also teaches the secondary efficacy endpoint is the proportion of FSGS patients experiencing a UP/C ratio ≤1.5 g/g and >40% reduction from baseline in UP/C at Week 8 over a range of dose levels compared to treatment with irbesartan as active control (secondary outcome measures).
Thus Retrophin teaches a method of treating a subject with focal segmental glomerulosclerosis (FSGS) comprising for a subject weighing less than or equal to 50 kg orally administering 200 mg or 400 mg of sparsentan to the subject once a day; or for a subject weighing more than 50 kg, orally administering 400 mg or 800 mg of sparsentan to the subject once a day, wherein the subject has a baseline UP/C ratio of 1.0 g/g or more, and wherein the subject’s urine protein to creatinine (UP/C) ratio is reduced by 40% or more relative to the subject’s baseline UP/C ratio.
Retrophin does not teach administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day in a 50 kg or less subject; or administering an initial dose of 400 mg of sparsentan to the subject once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 800 mg of sparsentan to the subject once a day in a more than 50 kg subject.
Although Retrophin does not teach administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day in a 50 kg or less subject; or administering an initial dose of 400 mg of sparsentan to the subject once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 800 mg of sparsentan to the subject once a day in a more than 50 kg subject, Retrophin specifically teaches administering 200 mg or 400 mg of sparsentan to a subject weighing less than or equal to 50 kg orally once a day; or orally administering 400 mg or 800 mg of sparsentan to a subject weighing more than 50 kg once a day, for focal segmental glomerulosclerosis (FSGS).
Thus Retrophin teaches administering the same amounts of the compounds as claimed. Although Retrophin does not teach starting with a lower dosages followed by administering a higher dosage, it is within the skill of an ordinary artisan to determine an appropriate treatment regimen such that optimal results are achieved. Furthermore, it has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
Thus in the absence of secondary considerations such as unexpected results or a demonstration of criticality, orally administering an initial dose of 200 mg of sparsentan once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 400 mg of sparsentan once a day in a 50 kg or less subject; or administering an initial dose of 400 mg of sparsentan once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 800 mg of sparsentan once a day in a more than 50 kg subject, is rendered obvious over the cited prior art teachings.
With respect to the claims that recite treatment beyond 8 weeks, Retrophin teaches thar FSGS is a chronic condition which can progress to end-stage kidney disease over years (detailed description). Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to continue treatment indefinitely to reduce proteinuria and thus treat FSGS and prevent end-stage kidney disease.
Thus since the method of claims 45, 67 and 70 are rendered obvious as detailed above, the effects achieved by the methods as claimed are also rendered obvious. Thus reducing the subject’s UP/C ratio by the amounts as claimed in the time frame as claimed and reducing the subject’s UP/C ratio by the amounts as claimed as compared to treatment with irbesartan as claimed are rendered obvious since the same method rendered obvious over the prior art teachings will necessarily produce the same results and effects as claimed. Furthermore since the prior art teaches administration of the same amount of the compound as claimed, reducing the subject’s risk of worsening edema relative to treatment with an angiotensin receptor blocker as claimed is also rendered obvious. Moreover, claims 70-72 are rendered obvious since the prior art renders obvious the method as claimed and thus said method rendered obvious over the prior art teachings will necessarily result in complete remission as claimed. Thus administration of the same amount of the same compound for the treatment of the same disorder will necessarily have the same effects as claimed which is complete remission.
Thus, the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Claims 45-72 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. U.S. Publication No. 2015/0164865 (Provided on IDS) in view of Montane et al. (Pediatr Nephrol (2003) 18:772–777).
Claims 45-72 of the instant application claim a method of treating a subject with focal segmental glomerulosclerosis (FSGS) comprising (a) for a subject weighing less than or equal to 50 kg, (i) orally administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; (ii) after the initial 14-day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day; or (b) for a subject weighing more than 50 kg, (i) orally administering an initial dose of 400 mg of sparsentan to the subject once a day for a period of 14 days; (ii) after the initial 14-day period, orally administering a subsequent dose of 800 mg of sparsentan to the subject once a day, wherein the subject has a baseline UP/C ratio of 1.5 g/g or more, and wherein the subject’s urine protein to creatinine (UP/C) ratio is reduced by 40% or more relative to the subject’s baseline UP/C ratio.
Zhang et al. teaches a biphenyl sulfonamide compound which is a dual angiotensin and endothelin receptor antagonist, pharmaceutical compositions containing such compound, and methods of using such compound in the treatment of endothelin-dependent or angiotensin II-dependent disorders and other diseases (0002).
Zhang et al. teaches that angiotensin II (AngII) and endothelin-1 (ET-1) are two of the most potent endogenous vasoactive peptides currently known and are believed to play a role in controlling both vascular tone and pathological tissue remodeling associated with a variety of diseases including diabetic nephropathy, heart failure, and chronic or persistently elevated blood pressure (0004). Zhang et al. teaches that currently, angiotensin receptor blockers (ARBs), which block the activity of AngII, are widely used as a treatment for diabetic nephropathy, heart failure, chronic or persistently elevated blood pressure, and there is a growing body of data that demonstrates the potential therapeutic benefits of ET receptor antagonists (ERAs) in blocking ET-1 activity (0004). Zhang et al. teaches that it is also known that AngII and ET-1 work together in blood pressure control and pathological tissue remodeling, for example, ARBs not only block the action of AngII at its receptor, but also limit the production of ET-1, and similarly, ERAs block ET-1 activity and inhibit the production of AngII (0005). Zhang et al. teaches that simultaneously blocking AngII and ET-1 activities may offer better efficacy than blocking either substance alone (0005).
Zhang et al. teaches the compound of formula I has the following structure:
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which is sparsentan (as identified on page 11 of the instant specification) (page 1 [0008]). Zhang et al. teaches that the compound of formula I and salts thereof are antagonists of both endothelin (especially, ET-1) and angiotensin II (especially, subtype AT1) receptors (“dual angiotensin endothelin receptor antagonists”) and are useful in treatment of conditions associated with increased ET levels and/or increased angiotensin II levels and of all endothelin-dependent or angiotensin II-dependent disorders (0043).
Zhang et al. further teaches that the compound of formula I is also useful in the treatment of disorders related to renal, glomerular and mesangial cell function, including acute (such as ischemic, nephrotoxic, or glomerulonephritis) and chronic (such as diabetic, hypertensive or immune-mediated) renal failure, diabetic nephropathy, glomerular injury, renal damage secondary to old age or related to dialysis, nephrosclerosis (especially hypertensive nephrosclerosis), nephrotoxicity (including nephrotoxicity related to imaging and contrast agents and to cyclosporine), renal ischemia, primary vesicoureteral reflux, glomerulosclerosis and the like (0044).
Zhang et al. teaches that the dosing regimen of the compound of formula I is administered for a period of time, which time period can be, for example, from at least about 4 weeks to at least about 8 weeks, from at least about 4 weeks to at least about 12 weeks, from at least about 4 weeks to at least about 16 weeks, or longer (0103).
Zhang et al. further teaches that an effective amount of the compound of formula I (sparsentan) may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a human of from about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably from about 0.5 to about 25 mg/kg of body weight (or from about 1 to about 2500 mg, preferably from about 100 to about 800 mg) of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day [0125]. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition [0125]. Zhang et al. further teaches that preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to endothelin-dependent or angiotensin II-dependent disorders [0125].
Claims 36-40 of Zhang et al. claim a method of treating glomerulosclerosis comprising administering to a subject in need thereof an effective amount of a compound of Formula I (sparsentan) or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of Formula I, or pharmaceutically acceptable salt thereof, administered to the subject is from about 200 mg/day to about 800 mg/day.
Thus Zhang et al. specifically teaches and claims a method of treating a subject with glomerulosclerosis comprising orally administering from about 200 mg/day to about 800 mg/day of sparsentan to the subject to treat the glomerulosclerosis.
Zhang et al. does not specifically teach focal segmental glomerulosclerosis (FSGS). Zhang does not teach treating a subject having a baseline UP/C ratio equal to or greater than 1.5 g/g. Zhang does not teach that the subject’s UP/C ratio is reduced by 40% or more relative to the subject’s baseline UP/C ratio. Zhang et al. does not teach administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day in a 50 kg or less subject; or administering an initial dose of 400 mg of sparsentan to the subject once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 800 mg of sparsentan to the subject once a day in a more than 50 kg subject.
Although Zhang et al. does not specifically teach focal segmental glomerulosclerosis (FSGS) or treating a subject having a baseline UP/C ratio equal to or greater than 1.5 g/g, Zhang et al. specifically teaches treating glomerulosclerosis comprising administering to a subject in need thereof an effective amount of a compound of Formula I (sparsentan). Thus, it would have been obvious to a person of ordinary skill in the art to treat all types of glomerulosclerosis to all patients in need thereof.
Montane et al. teaches that nephrotic syndrome progresses to focal segmental glomerulosclerosis (FSGS) and chronic renal failure (page 772). Montane et al. teaches the use of angiotensin blockade in patients with FSGS (page 772). Thus Montane et al. teaches that subjects with the type of focal segmental glomerulosclerosis (FSGS) benefit from angiotensin blockade for the treatment of glomerulosclerosis. Montane et al. teaches that biochemical parameters used to monitor the response to treatment included the degree of proteinuria and the serum albumin (page 774). Proteinuria was quantitated by the random UP/C, validated as an accurate reflection of daily proteinuria (page 774). Montane et al. teaches that nephrotic-range proteinuria exceeds a UP/C >2.0 mg/mg, while normal proteinuria is less than 100 mg/m2 per day or UP/C <0.2 (page 774). Montane et al. teaches that change in proteinuria was the primary measure of treatment response as determined by the urine protein/creatinine ratio (UP/C mg/mg) wherein normal is considered ≤0.2–0.6 and nephrotic-range proteinuria is ≥2.0 (page 775 Figure 2). Montane et al. teaches that the addition of angiotensin blockage treatment resulted in a decrease in proteinuria as demonstrated by a 72% decrease from baseline in UP/C and some patients achieved a complete remission by 6 months of treatment while other achieved a partial remission (page 775).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Zhang et al. which teaches a method of treating glomerulosclerosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula I (sparsentan) or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of Formula I, or pharmaceutically acceptable salt thereof, administered to the subject is from 200 mg/day to 800 mg/day, with the teachings of Montane et al. which teaches that subjects with the type of focal segmental glomerulosclerosis (FSGS) benefit from angiotensin blockade for the treatment of glomerulosclerosis wherein patients with FSGS present with nephrotic-range proteinuria which exceeds a UP/C >2.0 mg/mg, while normal proteinuria is considered ≤0.2–0.6. Thus based on the teachings of Zhang et al., one would have been motivated to choose any patient with glomerulosclerosis in need of treatment including those having FSGS with increased levels of proteinuria as measured by UP/C with nephrotic-range proteinuria that exceeds a UP/C >2.0 mg/mg. Moreover, since sparsentan is an angiotensin blocker as taught by Zhang et al. and Montane et al. demonstrates that treatment of patients with FSGS by angiotensin blocking results in reduction of proteinuria as demonstrated by reductions in UP/C, an ordinary skilled artisan would have reasonably expected that the method of Zhang et al. which administers an angiotensin blocker would also result in decreases in UP/C relative to the subject’s baseline UP/C ratio.
Thus a person of ordinary skill in the art following the teachings of Zhang et al. and administering sparsentan for the treatment of FSGS would reasonably expect said administration to lead to the reduction in proteinuria and thus slowing of kidney function decline as measured by UP/C ratio as claimed.
Although Zhang et al. does not specifically teach administering an initial dose of 200 mg of sparsentan to the subject once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 400 mg of sparsentan to the subject once a day in a 50 kg or less subject; or administering an initial dose of 400 mg of sparsentan to the subject once a day for a period of 14 days; and after the initial 14-day period, orally administering a subsequent dose of 800 mg of sparsentan to the subject once a day in a more than 50 kg subject, Zhang et al. specifically teaches administering to the subject from 200 mg/day to 800 mg/day; and further teaches an effective amount of the compound of formula I (sparsentan) may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a human of from about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably from about 0.5 to about 25 mg/kg of body weight (or from about 1 to about 2500 mg, preferably from about 100 to about 800 mg) of active compound per day, which may be administered in a single dose and it will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
Thus, Zhang et al. teaches administering the same amounts of the compounds as claimed, i.e. between about 200 mg/day and 800 mg/day, and moreover teaches that that factors such as body weight should be taken into consideration. Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious and well within the skill of an ordinary artisan to vary and/or optimize the dosages according to the guidance provided in Zhang et al. in order to arrive at the optimal dosages as claimed. Moreover, although Zhang et al. does not teach starting with a lower dosages followed by administering a higher dosage, it is within the skill of an ordinary artisan to determine an appropriate treatment regimen such that optimal results are achieved. It has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
Furthermore, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997).
Thus in the absence of secondary considerations such as unexpected results or a demonstration of criticality, orally administering an initial dosage of 200 mg followed by administering 400 mg after 14 days in a subject weighing less than or equal to 50 kg or orally administering an initial dosage of 400 mg followed by administering 800 mg after 14 days in a subject weighing more than 50 kg is rendered obvious over the cited prior art teachings.
Thus since the methods of claims 45, 67 and 70 are rendered obvious as detailed above, the effects achieved by the methods as claimed are also rendered obvious. Thus reducing the subject’s UP/C ratio by the amounts as claimed in the time frame as claimed and reducing the subject’s UP/C ratio by the amounts as claimed as compared to treatment with irbesartan as claimed to achieve complete remission as claimed are rendered obvious since the same method rendered obvious over the prior art teachings will necessarily produce the same results and effects as claimed. Furthermore since the prior art teaches administration of the same amount of the compound as claimed, reducing the subject’s risk of worsening edema relative to treatment with an angiotensin receptor blocker as claimed is also rendered obvious.
Thus, the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 1-44 are canceled. Claims 45-72 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM