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 .
Election/Restrictions
Applicant’s election without traverse of compound 1 (p. 86 of spec) in the reply filed 6/5/25 is acknowledged.
In the reply filed 2/4/26, Applicants amended claims 1-3 and 9. Claims 6 and 11-19 were canceled.
Claims 1-5, 7-10 are pending and under consideration.
Claim Rejections - Withdrawn
The rejection of Claims 1-12, 14-16 and 18-19 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn due to amendment of the claims.
The rejection of Claims 1-4 and 6-11 under 35 U.S.C. 103 as being unpatentable over The FDA NATPARA (FDA prescribing information Approved 2015 and revised 9/2018) in view of Bilezikian et al. (“Management of hypoparathyroidism: Present and future” J Clin Endocrinol Metab June 206, 101(6):2313-2324) is withdrawn due to amendment of the claims.
Claim Objections
Claim 1 is objected to because of the following informalities: “wherein titrating off the standard of case” in line 5 should be amened to “care”.
Claim 1 is objected to because of the following informalities: the first figure is blurry.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5 and 7-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite because the limitation “a nitrogen of -D” is unclear. The formulas of claim 1 do not contain a “-D” and it is unclear what the limitation is referencing. The metes and bounds of the formulas are unclear. For purposes of examination, the claim is interpreted to mean attachment to a nitrogen of SEQ ID NO: 51.
Claims 2-5 and 7-10 depend from claim 1 and are rejected.
Claim Rejections - 35 USC § 103-Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The rejection of claims 1-5 and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over The FDA NATPARA (FDA prescribing information Approved 2015 and revised 9/2018) in view of Bilezikian et al. (“Management of hypoparathyroidism: Present and future” J Clin Endocrinol Metab June 206, 101(6):2313-2324) and Sprogoe et al. (WO2018/060312,cited on IDS) is maintained.
Please note that the limitation “standard of care” is defined in the specification and is well known in the art to include calcium and active vitamin D supplementation [PGPUB0012].
With respect to claim 1 and “a method of treating or controlling patient suffering from hypoparathyroidism”, the FDA teaches NATPARA for subcutaneous injection for treatment of hypoparathyroidism (Indication and usage), meeting the limitation of claims 1 (in part) and 7. NATPARA is a parathyroid hormone and meets the limitation of “PTH compound”.
With respect to the limitation “administering to the patients single daily administrations of a PTH compound”, the FDA teaches once daily subcutaneous injections (para. 2.3, p. 3).
The FDA teaches the dose will generally be the dose that maintains total serum calcium (albumin-corrected) within the lower half of the normal range (i.e., between 8 and 9 mg/dL) without the need for active forms of vitamin D and with calcium supplementation sufficient and individualized to meet the patient’s daily requirements. Doses of active forms of vitamin D and calcium supplements will need to be adjusted when using NATPARA (para. 2.1, p. 3). The FDA teaches to adjust dose of active vitamin D or calcium supplement or both based on serum calcium value and clinical assessment (i.e., signs and symptoms of hypocalcemia or hypercalcemia). Suggested adjustments to active vitamin D and calcium supplement based on serum calcium levels are provided below (p. 4):
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The FDA teaches that there is a risk of hypercalcemia and treatment is per standard practice and to consider holding and lowering the dose of NATPARA (p. 7, para 5.3).
The FDA does not teach titrating at least some of the patients off a standard of care within four weeks from the time the first dose of the PTH was administered, however the teachings of Bilezikian et al. cure this deficiency.
Bilezikian et al. teach that conventional management of hypoparathyroidism has focused upon maintaining the serum calcium with oral calcium and active Vitamin D, often requiring high doses and giving rise to concerns about long term consequences including renal and brain calcifications (Abstract). Bilezikian et al. teach a time course after PTH (1-84) was administered wherein serum calcium was monitored after injection, 71% developed hypercalcemia at one or more measuring during a 24 hour period (p. 2320, top of 1st col.). Bilezikian et al. a pivotal phase III -trial of rhPTH (1– 84) in hypoparathyroidism was reported wherein this multicenter, multinational, placebo-controlled, double blinded trial compared rhPTH (1– 84) administered with a titration algorithm (50 g could be increased to 75 g or to 100 g). The results of the study showed that 53% of study subjects receiving rhPTH (1– 84) met this triple primary end point, whereas only 2% of study subjects receiving placebo did. (p. 2320, 2nd col., last para.). The trial’s triple primary end point was: 1) reduction of calcium supplementation by 50% or more; 2) reduction of active vitamin D supplementation by 50% or more; and 3) maintenance of stable serum calcium levels within the normal range. The secondary endpoint, the proportion of subjects who were able to eliminate all active vitamin D supplementation while reducing the dose of oral calcium to no more than 500 mg/d was also highly significant in favor of the study subjects who received rhPTH (1–84): 43 vs. 5% (p. 2320, bottom of 2nd col.). Bilezikian et al. teach the official recommendations are stated in the package insert to initiate rhPTH (1– 84) at 50 g once daily as a sc injection into the thigh and to concomitantly decrease the dose of active vitamin D by 50%. Serum calcium (and albumin) concentrations are to be monitored every 3–7 days after initiation of therapy and after each dose change. The dose of rhPTH (1– 84) is to be titrated every 4 weeks with the goal to discontinue active vitamin D and to reduce oral calcium supplements to an amount as low as 500 mg/d while keeping serum calcium within the low-normal range (p. 2321, 2nd col, 1st para.).
With respect to the limitation “and titrating at least some of the patients off a standard of care within four weeks from the time the first dose of the PTH was administered…and wherein in at least some of the patients calcium supplementation is eliminated”, it would have been obvious to a person of ordinary skill in the art to titrate a hypoparathyroidism patient off calcium and vitamin D supplementation within 4 weeks of initiating PTH therapy. A person would look to the teachings of the FDA which instructs clinicians to decrease using active forms of Vitamin D after injection, to begin measuring and tapering levels of calcium at 3 to 7 days post injection and to hold or reduce calcium supplementation in response to calcium levels. A person of ordinary skill in the art would also have a motivation to titrate at least some of the patients off the standard of care because Bilezikian et al. teach a time course after PTH (1-84) was administered wherein serum calcium was monitored after injection, 71% developed hypercalcemia at one or more measuring during a 24 hour period. Therefore, the prior art teaches that the levels of calcium and vitamin D should be monitored and titrated down. Importantly, the method and timing and titration off active ingredients is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). There is a reasonable expectation of success given that the administering PTH and methods for monitoring and titrating the calcium and vitamin D are taught by the prior art.
The references do not teach the PTH compound or the dose of the PTH compound (claim 5). However, the teachings of Sprogoe et al. cure this deficiency.
Sprogoe et al. teach a need for improved PTH based therapies for hypoparathyroidisms. Sprogoe et al. teach the object of the invention is to provide for symptom control with a lower administered dose (p. 4, lines 4-5). Sprogoe et al. teach a need for a more convenient and safer treatment of hypoparathyroidism with reduces side effects (p. 4, lines 9-10). Sprogoe et al. teach the PTH compound of the invention is capable of achieving a stable plasma profile of PTH (p. 4, lines 20-22).
Sprogoe et al. teach (bottom of p. 94):
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Sprogoe et al. teach the PTH is SEQ ID NO: 51, which is identical to instantly claimed SEQ ID NO: 51 (p. 51; p. 16; p. 39; p. 39, line 20; p. 45).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to use the PTH compound of Sprogoe et al. for the treatment of hypoparathyroidism because Sprogoe et al. teach the PTH compound of the invention provides symptom control with a lower administered dose. A person of ordinary skill in the art would understand that where therapeutically effective, lower dosages of medications are preferred in order to minimize side effects, improve patient compliance and reduce treatment burden. Accordingly, substituting a PTH compound with the lower dose PTH compound would have been obvious choice to one of ordinary skill in the art. There is a reasonable expectation of success given that the PTH compound of Sprogoe et al. displayed a stable plasma profile.
With respect to claims 2-3 and 9-10, the method and timing and titration off active ingredients is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). In addition to the teachings above, The FDA teaches the dose of NATPARA should be individualized based on total serum calcium (albumin-corrected) and 24-hour urinary calcium excretion. The FDA teaches the recommended NATPARA dose is the minimum dose required to prevent both hypocalcemia and hypercalciuria. The FDA teaches this dose will generally be the dose that maintains total serum calcium within the lower half of the normal range (i.e., between 8 and 9 mg/dL) without the need for active forms of vitamin D and with calcium supplementation sufficient and individualized to meet the patient’s daily requirements. Doses of active forms of vitamin D and calcium supplements will need to be adjusted when using NATPARA. It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize titration of calcium and vitamin D after PTH administration to arrive at the protocol of claims 2-3 and 9-10. Furthermore, it would have been obvious to a person of ordinary skill in the art to titrate a hypoparathyroidism patient off calcium and vitamin D supplementation as indicated in claims 2-3 and 9-10. A person would look to the teachings of the FDA which instructs clinicians to decrease using active forms of Vitamin D after injection and to begin measuring and tapering levels of calcium at 3 to 7 days post injection. A person of ordinary skill in the art would also have a motivation to titrate a patient off the standard of care because Bilezikian et al. teach a time course after PTH (1-84) was administered wherein serum calcium was monitored after injection, 71% developed hypercalcemia at one or more measuring during a 24 hour period. Therefore, the prior art teaches that the levels of calcium and vitamin D should be monitored and titrated down. There is a reasonable expectation of success given that the administering PTH and methods for monitoring and titrating the calcium and vitamin D are taught by the prior art.
With respect to claim 4, The FDA teaches single dose of 25 mcg per dose strength (para. 3, p. 5).
With respect to claim 5, the dose of the active agent for treating a disease/disorder is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). In the instant case, the FDA teaches single dose of 25 mcg per dose strength (para. 3, p. 5) and Sprogoe et al. teach the object of the invention is to provide for symptom control with a lower administered dose (p. 4, lines 4-5). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the dose, to arrive at the dose of claim 5.
With respect to claim 8, the FDA teaches administration using a pen delivery device (i.e. Q-Cliq pen) para. 2.7, p. 5).
Response to Arguments
Applicant's arguments filed 2/4/26 have been fully considered but they are not persuasive. Applicants argue that result effective variables are numeric parameters such as temperature or concentration of a reagent for which it is known they can be varied to affect the outcome of the process. Applicants argue that active Vitamin d and calcium supplementation are not a results driven variables analogous to temperature and concentration. Applicants argue that whether and to what extent active Vitamin D and calcium can be reduced is dependent on achieving an adequate level of control of serum levels with Natpara and the timing and extent of reductions are limited by a patients response to Natpara treatment, not parameters that a practitioner can vary at will to optimize treatment by Natpara.
This argument was considered but is not persuasive because Natpara teaches administering PTH, measuring serum calcium, reducing active Vitamin D and reducing or holding calcium supplementation and continue monitoring. In other words, the clinician is deciding how much to reduce and when to reduce it based on feedback. The claimed timing and extent of vitamin D and calcium reduction are not fixed outcomes but parameters that are actively adjusted by the clinician based on measured levels. Therefore, the adjustments constitutes optimization of treatment variables.
Applicants argue that some hypoparathyroid patients require low level calcium supplementation to compensate for a deficit in dietary intake (lactose intolerance). Because in such patients such a level of supplementation approximates to intake of calcium from a normal diet and is not considered therapeutic nor invoking of abnormal risk of calcification.
This is not persuasive because the claims are directed to titration off standard of care treatment of hypoparathyroidism. Whether a patient received modest nutritional calcium supplementation to address ordinary dietary deficiencies is irrelevant to whether the patient has been titrated off a standard of care in response to a drug. Furthermore, the claim does not require all calcium supplementation is eliminated in all patients.
Applicants argue that early titration off active vitamin D and calcium supplementation is highly advantageous for the patient because of convenience and side effects. Applicants argue that the result achieved with the claimed agent is far superior to Natpara because upward adjustment of Natpara implies a serum calcium below 8 mg/dl, a level also calling for upward adjustment of calcium and Vitamin D supplementation. Applicants argue that there is no indication that any of the subjects in the Natpara trial were titrated down to zero for both vitamin D and calcium supplementation as was the case for 50% of the subjects in the phase II trial of the current agent. Applicants argue that characterizations of Natpara as an adjunct to calcium and vitamin D indicates its not expected to replace those supplements entirely. Applicants argue there is no reasonable expectation of success from the cited art that treatment of hypoparathyroidism with a different agent than Natpara could normalize serum calcium levels within an acceptable range more quickly and stably than was the case for Natpara. Applicants argue that the claimed methods allow most of the patients to be completely titrated off active vitamin D and calcium either completely or to a level comparable to a normal diets represents unexpected results and there is not basis to expect that such an improvement relative to Natpara could be achievable.
These arguments were considered but are not persuasive because the combined prior art teaches PTH replacement in hypoparathyroid treatment, reduction or discontinuation in active vitamin D, reduction or holding of calcium supplementation and use of the exact claimed conjugate for treating hypoparathyroidism. Natpara teaches reduction/discontinuation of vitamin D and calcium. The exact PTH compound is taught by Sprogoe et al. and was known for treating hypoparathyroidism. The art recognized the need of reducing Vitamin D and calcium supplementation in this patient population. Importantly, the claims require only “at least some patients”. The claims do not require a complete discontinuation of Vitamin D and calcium supplementation in all patients. Furthermore, Applicants arguments of evidence of superior clinical outcomes including complete discontinuation of supplementation in 50% of the subject is not commensurate in scope with the claims which requires only “at least some of the patients” are titrated off a standard of care. Moreover, the prior art teaches the same conjugate. Therefore, the same conjugate, administered to the same patient population would have the same properties. For the reasons presented above, the rejection is maintained.
Double Patenting-Maintained
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.
The rejection of claims 1-5 and 7-10 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-68 of copending Application No. 18/693,510 (reference application) is maintained. Although the claims at issue are not identical, they are not patentably distinct from each other. The copending application claims a method of treating a patient having increased bone mineral density comprising administering a long-acting PTH compound, wherein the patient having increased bone mineral density is a patient having hypothyroidism (claims 37-48). The copending Application also claims a method of treating hypoparathyroidism with a long acting PTH wherein the PTH compound meets the limitations of instant claims. The copending application claims monitoring and titrating the levels of calcium and vitamin D (claims 52-67). It would have been obvious to optimize the dose and titration time of the standard of care to arrive at the range of the instant claims. There is a reasonable expectation of success given that titration of calcium and vitamin D are known in the art in response to PTH treatment.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 2/4/26 have been fully considered but they are not persuasive. Applicants argue that the copending application has a later filing dates and if the present application is allowable, the rejection should be withdrawn.
This argument was considered but is not persuasive as no allowable subject matter has been indicated. Therefore, the rejection is maintained.
The rejection of claims 1-5 and 7-10 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,403,182 in view of The FDA NATPARA (FDA prescribing information Approved 2015 and revised 9/2018) and Bilezikian et al. (“Management of hypoparathyroidism: Present and future” J Clin Endocrinol Metab June 206, 101(6):2313-2324) is maintained.
The USPN claims a liquid formulation comprising a PTH compound comprising SEQ ID NO: 51 and a method of treating hypoparathyroidism with the PTH compound. The PTH compound of the USPN meets the limitations of claims. The USPN does not claim the method of titrating off the stand or care (calcium and vitamin D), however the teachings of The FDA and Bilezikian et al. cure this deficiency.
The teachings of The FDA and Bilezikian et al. are presented in detail above (please see 103 rejection above).
With respect to the limitation “and titrating the patient off a standard of care within four weeks from the time the first dose of the PTH was administered”, it would have been obvious to a person of ordinary skill in the art to titrate a hypoparathyroidism patient off calcium and vitamin D supplementation within 4 weeks of initiating PTH therapy. A person would look to the teachings of the FDA which instructs clinicians to decrease using active forms of Vitamin D after injection and to begin measuring and tapering levels of calcium at 3 to 7 days post injection. A person of ordinary skill in the art would also have a motivation to titrate a patient off the standard of care because Bilezikian et al. teach a time course after PTH (1-84) was administered wherein serum calcium was monitored after injection, 71% developed hypercalcemia at one or more measuring during a 24 hour period. Therefore, the prior art teaches that the levels of calcium and vitamin D should be monitored and titrated down. Importantly, the method and timing and titration off active ingredients is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). There is a reasonable expectation of success given that the administering PTH and methods for monitoring and titrating the calcium and vitamin D are taught by the prior art.
With respect to claims 4 and 5, the dose of the active agent for treating a disease/disorder is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the dose, to arrive at the dose of claims 4 and 5.
Therefore, the combined references make obvious the limitations of claims 1-5 and 7-10.
Response to Arguments
Applicant's arguments filed 2/4/26 have been fully considered but they are not persuasive. Applicant argue the rejection raises the same issues as disclosed in the 103 above.
The rejection is maintained for the reasons presented above.
The rejection of claims 1-5 and 7-10 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 31-33 of copending Application No. 17/055, 695in view of The FDA NATPARA (FDA prescribing information Approved 2015 and revised 9/2018) and Bilezikian et al. (“Management of hypoparathyroidism: Present and future” J Clin Endocrinol Metab June 206, 101(6):2313-2324) is maintained.
The copending application claims a method of treating, controlling or delaying a disease with PTH in a human patient, wherein the PTH conjugate is a formula that comprises SEQ ID NO: 51, wherein the disease is hypoparathyroidism and is administered as one subcutaneous injection (claims 1-9). The PTH conjugate meets the limitations of the instant claims. The USPN does not claim the method of titrating off the stand or care (calcium and vitamin D), however the teachings of The FDA and Bilezikian et al. cure this deficiency.
The teachings of The FDA and Bilezikian et al. are presented in detail above (please see 103 rejection above).
With respect to the limitation “and titrating the patient off a standard of care within four weeks from the time the first dose of the PTH was administered”, it would have been obvious to a person of ordinary skill in the art to titrate a hypoparathyroidism patient off calcium and vitamin D supplementation within 4 weeks of initiating PTH therapy. A person would look to the teachings of the FDA which instructs clinicians to decrease using active forms of Vitamin D after injection and to begin measuring and tapering levels of calcium at 3 to 7 days post injection. A person of ordinary skill in the art would also have a motivation to titrate a patient off the standard of care because Bilezikian et al. teach a time course after PTH (1-84) was administered wherein serum calcium was monitored after injection, 71% developed hypercalcemia at one or more measuring during a 24 hour period. Therefore, the prior art teaches that the levels of calcium and vitamin D should be monitored and titrated down. Importantly, the method and timing and titration off active ingredients is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). There is a reasonable expectation of success given that the administering PTH and methods for monitoring and titrating the calcium and vitamin D are taught by the prior art.
With respect to claims 4 and 5, the dose of the active agent for treating a disease/disorder is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the dose, to arrive at the dose of claims 4 and 5.
Therefore, the combined references make obvious the limitations of claims 1-5 and 7-10.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 2/4/26 have been fully considered but they are not persuasive. Applicant argue the rejection raises the same issues as disclosed in the 103 above.
The rejection is maintained for the reasons presented above.
The rejection of claims 1-5 and 7-10 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11,590,207 in view of The FDA NATPARA (FDA prescribing information Approved 2015 and revised 9/2018) and Bilezikian et al. (“Management of hypoparathyroidism: Present and future” J Clin Endocrinol Metab June 206, 101(6):2313-2324) is maintained.
The USPN claims a method of treating or controlling hypoparathyroidism in a mammalian patient, comprising administering a controlled release PTH compound by subcutaneous injection no more frequently than once every 24 hours with a dosage that corresponds to 20-40% of the molar equivalent dose of PTH 1-84 which is required to maintain a serum albumin-adjusted calcium level in serum of above 8.5 mg/dL over a 24 hour period in humans compound. The USPN claims the patient is human. The PTH compound of the USPN meets the limitations of claims. The USPN does not claim the method of titrating off the stand or care (calcium and vitamin D), however the teachings of The FDA and Bilezikian et al. cure this deficiency.
The teachings of The FDA and Bilezikian et al. are presented in detail above (please see 103 rejection above).
With respect to the limitation “and titrating the patient off a standard of care within four weeks from the time the first dose of the PTH was administered”, it would have been obvious to a person of ordinary skill in the art to titrate a hypoparathyroidism patient off calcium and vitamin D supplementation within 4 weeks of initiating PTH therapy. A person would look to the teachings of the FDA which instructs clinicians to decrease using active forms of Vitamin D after injection and to begin measuring and tapering levels of calcium at 3 to 7 days post injection. A person of ordinary skill in the art would also have a motivation to titrate a patient off the standard of care because Bilezikian et al. teach a time course after PTH (1-84) was administered wherein serum calcium was monitored after injection, 71% developed hypercalcemia at one or more measuring during a 24 hour period. Therefore, the prior art teaches that the levels of calcium and vitamin D should be monitored and titrated down. Importantly, the method and timing and titration off active ingredients is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). There is a reasonable expectation of success given that the administering PTH and methods for monitoring and titrating the calcium and vitamin D are taught by the prior art.
With respect to claims 4 and 5, the dose of the active agent for treating a disease/disorder is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the dose, to arrive at the dose of claims 4 and 5.
Therefore, the combined references make obvious the limitations of claims 1-5, 7-10.
Response to Arguments
Applicant's arguments filed 2/4/26 have been fully considered but they are not persuasive. Applicant argue the rejection raises the same issues as disclosed in the 103 above.
The rejection is maintained for the reasons presented above.
The rejection of claims 1-5 and 7-10 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,759,504 in view of The FDA NATPARA (FDA prescribing information Approved 2015 and revised 9/2018) and Bilezikian et al. (“Management of hypoparathyroidism: Present and future” J Clin Endocrinol Metab June 206, 101(6):2313-2324) is maintained.
The USPN claims a PTH compound suitable for subcutaneous administration to a mammal wherein the subcutaneous administration has a pharmacokinetic profile exhibiting a peak to trough ratio of free PTH of less than 4 in plasma within one daily injection interval, wherein the PTH compound is formula 1a. , wherein the device is a pen device and the mammal is a human (claim 1-12. The PTH compound of the USPN meets the limitations of claims. The USPN does not claim the method of treating of controlling hypoparathyroidism and titrating off the stand or care (calcium and vitamin D), however the teachings of The FDA and Bilezikian et al. cure this deficiency.
Please note that MPEP 804 states: The portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. In the instant case, the USPN specification discloses the use of the PTH compound for treatment of hypoparathyroidism.
The teachings of The FDA and Bilezikian et al. are presented in detail above (please see 103 rejection above).
With respect to the limitation “and titrating the patient off a standard of care within four weeks from the time the first dose of the PTH was administered”, it would have been obvious to a person of ordinary skill in the art to titrate a hypoparathyroidism patient off calcium and vitamin D supplementation within 4 weeks of initiating PTH therapy. A person would look to the teachings of the FDA which instructs clinicians to decrease using active forms of Vitamin D after injection and to begin measuring and tapering levels of calcium at 3 to 7 days post injection. A person of ordinary skill in the art would also have a motivation to titrate a patient off the standard of care because Bilezikian et al. teach a time course after PTH (1-84) was administered wherein serum calcium was monitored after injection, 71% developed hypercalcemia at one or more measuring during a 24 hour period. Therefore, the prior art teaches that the levels of calcium and vitamin D should be monitored and titrated down. Importantly, the method and timing and titration off active ingredients is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). There is a reasonable expectation of success given that the administering PTH and methods for monitoring and titrating the calcium and vitamin D are taught by the prior art.
With respect to claims 4 and 5, the dose of the active agent for treating a disease/disorder is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the dose, to arrive at the dose of claims 4 and 5.
Therefore, the combined references make obvious the limitations of claims 1-5 and 7-10.
Response to Arguments
Applicant's arguments filed 2/4/26 have been fully considered but they are not persuasive. Applicant argue the rejection raises the same issues as disclosed in the 103 above.
The rejection is maintained for the reasons presented above.
Response to Amendment
The Declaration under 37 CFR 1.132 filed 2/4/26 is insufficient to overcome the rejection of claims based upon The FDA NATPARA (FDA prescribing information Approved 2015 and revised 9/2018) in view of Bilezikian et al. (“Management of hypoparathyroidism: Present and future” J Clin Endocrinol Metab June 206, 101(6):2313-2324) and Sprogoe et al. (WO2018/060312,cited on IDS) as set forth in the last Office action. The Declaration states that the Khan reference included a error and should state that 50% of TransCon PTH treated subjects achieved complete independence from conventional therapy (i.e. discontinuing both oral active Vitamin D and calcium) compared to placebo.
The Declaration was considered but is not persuasive for the reasons presented above in the Response to Arguments section of the 103 rejection. In particular, the combined prior art teaches PTH replacement in hypoparathyroid treatment, reduction or discontinuation in active vitamin D, reduction or holding of calcium supplementation and use of the exact claimed conjugate for treating hypoparathyroidism. Natpara teaches reduction/discontinuation of vitamin D and calcium and the art recognized the need of reducing Vitamin D and calcium supplementation in this patient population. Importantly, the claims require only “at least some patients”. Furthermore, Applicants arguments of evidence of superior clinical outcomes including complete discontinuation of supplementation in 50% of the subject is not commensurate in scope with the claims which requires only “at least some of the patients” are titrated off a standard of care. Moreover, the prior art teaches the same conjugate. Therefore, the same conjugate, administered to the same patient population would have the same properties.
Conclusion
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).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/TARA L MARTINEZ/Examiner, Art Unit 1654
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