Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Continued Examination under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission of RCE on December 18, 2025 and amendment after final filed on December 18, 2025 has been entered. Claims1-33 were canceled and claims 34-53 are pending in the instant application.
The restriction requirement was deemed proper and made FINAL in a previous office action. Claim 38 remains withdrawn from consideration as being drawn to a non-elected invention/species.
Claims 34-37, 39-53 are examined on the merits of this office action.
Maintained/Revised Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 34-37, 39-53 are rejected under 35 U.S.C. 103 as being unpatentable over ClinicalTrials (NCT03182699, Version 3, published online March 5, 2019, cited previously) in view of Eidman (International Journal of Nephrology and Renovascular Disease 2018:11 69–80, cited previously) as evidenced by Russo (International Journal of Nephrology Volume 2011).
Regarding claim 34,48 and 50, ClinicalTrials teaches a method of treating left ventricular hypertrophy in hemodialysis patients with administering Etelcalcetide (see Study Description). Regarding claims 35-36, 52, ClinicalTrials teaches patients on chronic hemodialysis treatment three times a week (see “Methods/design”, second paragraph). Regarding claims 37 and 53, ClinicalTrials teaches wherein the subject has received hemodialysis for at least 3 months (see Inclusion criteria, greater than or equal to 3 months). Regarding claims 39-40, ClinicalTrials teaches intravenous administration (which is also parenteral) (See “methods and design”, second paragraph). Regarding claim 42, ClinicalTrials teaches wherein the subject has secondary hyperparathyroidism (SHPT) (see “Specific Aim 1, page 3). Regarding claim 43, ClinicalTrials teaches a PTH level of greater than or equal to 300 pg/ml prior to treatment (see inclusion criteria, bulletin point 3).
Regarding claim 48, ClinicalTrials teaches treating patients with LVH and on chronic hemodialysis via intravenous administration of etelcalcetide (see “Method/Design”, paragraph 2).
Regarding claim 50, ClinicalTrials teaches treating patients with LVH and on chronic hemodialysis via intravenous administration of etelcalcetide for 12 months (see “Method/Design”, paragraph 2).
ClinicalTrials is silent to wherein the starting dose of etelcalcetide is 5 mg three times per week.
Eidman discloses of Phase I and II clinical studies of etelcalcetide in human subjects, in which participants received single doses of 0.5, 2, 5 or 10 mg. The 5 mg dose produced dose dependent reductions in PTH and associated physiological markers, with effects observed during the interdialytic period when multiple doses were administered. Eidman also teaches similar sustained effects in hemodialysis patients, confirming the clinical relevance of the 5 mg dose (see page 71, right column, “Phase I and II studies…”. Eidman teaches “Etelcalcetide was administered IV thrice weekly starting at a 5 mg dose and titrated based on PTH and albumin-corrected serum calcium levels to target a relatively narrow PTH range of 150–300 pg/mL. The mean decrease in PTH was 53.6%, with 89.0% of participants achieving a 30% or greater reduction from baseline. Overall, etelcalcetide was characterized as being well tolerated” (see page 72, left column, first paragraph). Eidman additionally teaches reduction is FGF23 (see page 72, right column, second paragraph) which is considered associated with increased LVH (see Russo, see page 3, left column, last 20 lines of section 8).
One of ordinary skill in the art would have been motivated to apply the 5 mg dose regimen taught by Eidman to the treatment method disclosed by ClinicalTrials, as both involve etelcalcetide administration in hemodialysis patients, and the 5 mg dose is shown to be pharmacologically active, well tolerated, and compatible with the hemodialysis schedule (three times per week). There would have been a reasonable expectation of success in using this dose for treating LVH in sHPT patients, based on the known systemic cardiovascular effects of PTH suppression and FGF23 which is associated with LVH.
A person of ordinary skill in the art would have recognized that etelcalcetide was already clinically validated for controlling SHPT related biomarkers, including PTH and FGF23, in the same hemodialysis patient population recited in the instant claims. Because ClinicalTrials expressly identifies LVH related cardiac imaging endpoints in these patients and Russo evidences that elevated FGF23 levels are associated with LVH progression, it would have been reasonable to expect that administration of the known clinically effective etelcalcetide regimen would predictably provide at least some improvement in LVH associated cardiovascular parameters. Absolute predictability is not required for finding of obviousness, rather only a reasonable expectation of success.
Furthermore, the selection of a starting dose of 5 mg three times per week would have constituted routine optimization of a result effective variable. Eidman teaches that multiple doses of etelcalcetide in the range of .5 to 10 mg produce dose dependent physiological effects, and the 5 mg dose is specifically show to be effective in reducing PTH along with other factors including FGF23. Given that etelcalcetide is administered IV three times per week in the ClinicalTrials, and that Eidman provides clinical support for starting at 5 mg, one of ordinary skill in the art would have found it obvious to select the 5 mg dose as a matter of routine experimentation to achieved the desired clinical effect on cardiovascular endpoints. Furthermore, Eidman teaches that etelcalcetide dosing within the disclosed range produced dose dependent physiological effects on PTH and related biomarkers. Therefore, optimization of the starting dose to achieve the desired therapeutic response would have constated no more than routine optimization involving a result effective variable (see MPEP 2144).
Furthermore, although ClinicalTrials does not explicitly use the term “human subject”, the reference repeatedly describes the population as “hemodialysis patients” undergoing imaging procedures such as cardiac MRI and echocardiography-tools used in human medicine. Thus, the limitation “in a human subject” is inherently satisfied.
Accordingly, the method of administering etelcalcetide at a starting dose of 5 mg three times per week to a human subject for the treatment of LVH, as recited in instant claims 34, 48 and 50 would have been obvious in view of the combined teachings of ClinicalTrials and Eidman.
Regarding the limitation of “slowing progression of LVH” and “delaying the progression” in claims 48 and 50, ClinicalTrials in view of Eidman teaches the same method of the instant claims (same active method steps) and thus these effects will inherently be achieved as a result of practicing the method of ClinicalTrials and Eidman.
Regarding claims 41, 49, 51, the limitation “wherein etelcalcetide when provided to the subject for a period of 12 months is effective to alleviate progression of left ventricle hypertrophy by a median of about 6.7 g/m2 relative to left ventricle hypertrophy before said administering”, ClinicalTrials in view of Eidman teaches the same method of the instant claims including 12 months administration (see “methods/design”, paragraph 2), same dosing of etelcalcetide and same patient population and thus, these effects will inherently be achieved as a result of practicing the method of ClinicalTrials in view of Eidman.
Regarding claim 44, “wherein etelcalcetide is at a dose that achieves blood PTH level of less than 300 pg/ml, ClinicalTrials in view of Eidman teaches the same method of the instant claims (same active method steps and dosing) and thus these effects will inherently be achieved as a result of practicing the method of ClinicalTrials in view of Eidman.
Regarding claim 45-47, “wherein etelcalcetide is at a dose that achieves a blood parathyroid hormone (PTH) level of between about 100 pg/mL to about 300 pg/mL” (claim 45); wherein etelcalcetide slows development of cardiac fibrosis in the subject (claim 46); “wherein the etelcalcetide alleviates progression of left ventricle hypertrophy in the subject, as measured by left ventricular mass index through cardiac magnetic resonance imaging (cMRI)” (claim 47), ClinicalTrials in view of Eidman teaches the same method of the instant claims (same active method steps, same dosing and patient population) and thus these effects will inherently be achieved as a result of practicing the method of ClinicalTrials and Eidman.
Response to Applicant’s Arguments
Applicant argues “Applicant respectfully disagrees with the reasoning in the Office Action and submits that, here, there is no reasonable expectation of success. As stated in M.P.E.P. § 2143(I)(A), a reasonable expectation of success is a requirement for a proper determination of obviousness. See also, e.g., In re O'Farrell, 853 F.2d 894, 904 (Fed. Cir. 1988). This requirement "refers not only to the expectation that prior art elements are capable of being physically combined, but also that the combination would have worked for its intended purpose." See, M.P.E.P. § 2143(I)(A) (citing DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 90 USPQ2d 1865 (Fed. Cir. 2009))(emphasis added). Applicant submits that one of ordinary skill would not have reasonably expected etelcalcetide to be useful in a "method of treating left ventricle hypertrophy in a human subject" in view of the cited references. At the outset, ClinicalTrials is merely a clinical trial registration. This posting describes a study that was ongoing and yet been completed as of the publication date of March 5, 2019. For instance, ClinicalTrials indicates the study status was "Active, not recruiting" with an estimated Primary Completion date of November 1, 2019 and an estimated Study Completion date of December 1, 2020. ClinicalTrials at Study Status. Applicant respectfully submits that a person of ordinary skill in the art would understand that this clinical trial registration is merely a description of proposed or ongoing research-it is not evidence that the proposed research will succeed. The assumption that ClinicalTrials discloses a "method of treating left ventricular hypertrophy" is contrary to the very nature of clinical trials, which are conducted precisely because the outcome is uncertain. Clinical trials, particularly randomized controlled trials, are the gold standard for determining whether a therapeutic intervention actually works. They are conducted when there is scientific uncertainty about whether a proposed treatment will be effective. The mere fact that researchers hypothesize a particular outcome and design a study to test that hypothesis does not mean that one of ordinary skill in the art would have a reasonable expectation that the hypothesis is correct. Indeed, ClinicalTrials provides no discussion of the outcomes of the clinical trial.
Additionally, the Federal Circuit's decision in OSI Pharmaceuticals, LLC v. Apotex Inc., 939 F.3d 1375 (Fed. Cir. 2019), squarely forecloses any argument that the mere disclosure of a clinical study-without accompanying efficacy results-can provide a person of ordinary skill in the art with a reasonable expectation of success in achieving the claimed therapeutic method.
In OSI, the PTAB had found obviousness based largely on (1) a Form 10-K stating that erlotinib (Tarceva®) was being evaluated in clinical trials, including for non-small cell lung cancer (NSCLC), and (2) general prior-art references describing EGFR inhibitors as potential anticancer agents. Id. at 1379-80. Critically, none of these references reported any efficacy results for erlotinib in NSCLC patients. The Federal Circuit reversed the PTAB's obviousness holding, stating that the prior art clinical trial disclosures did not provide a reasonable expectation of success because they lacked meaningful efficacy data. The court emphasized that the cited references "do not disclose any results" from the clinical trials and "provide no data or other promising information regarding erlotinib's efficacy in treating NSCLC." Id. at 1383-1384.
Applicants arguments have been fully considered but not found persuasive. With respect to Applicant argues that ClinicalTrials is merely a clinical trial registration and therefore does not teach a method of treating LVH, the Examiner respectfully disagrees. ClincialTrials expressly discloses a study evaluating administration of etelcalcetide to hemodialysis patients with left ventricular hypertrophy (LVH), including administration parameters, patient selection criteria, treatment duration and cardiovascular imaging endpoints. A prior is reference is not limited to embodiment’s proven clinically successful (see MPEP 2123).
Obviousness under 35 U.S.C. 103 does not require absolute predictability or demonstrated clinical success. Rather, the proper inquiry is whether the combined prior art would have provided one of ordinary skill in the art with a reason to pursue the claimed method with a reasonable expectation of success (see MPEP2143). ClinicalTrials demonstrates that person of ordinary skill in the art considered etelcalcetide a scientifically suitable candidate for treatment of LVH in dialysis patients. The reference discloses a specifically designed therapeutic protocol directed to the same disease state, same patient population, same route of administration and same treatment duration recited in the instant clams.
Furthermore, ClinicalTrials does not merely disclose a generalized research proposal, but rather a specifically designed therapeutic regimen directed to the same indication recited in the claims using the same pharmacologically active agent in the same dialysis population. Such disclosure evidences that those skilled in the art considered the claimed therapeutic approach sufficiently promising to warrant clinical investigation. Accordingly, ClinicalTrials constitutes relevant prior art.
With respect to Applicant’s arguments that “Clinical trials are conducted because outcomes are uncertain; therefore no reasonable expectation of success existed”, the Examiner respectively disagrees. Applicants argument improperly equates “reasonable expectation of success” with certainty of success. The law does not require absolute predictability in order to establish obviousness (see MPEP 2143.02, “Obviousness does not require absolute predictability of success”). ClinicalTrials and Eidman collectively provide sufficient basis for a reasonable expectation of success because Eidman teaches that etelcalcetide is pharmacologically active in hemodialysis patients; Eidman teaches IV administration three times weekly beginning at 5 mg; Eidman teaches substantial suppression of PTH and associated physiological markers (including FGF23 which is associated with LVH as evidenced by Russo); and ClinicalTrials teaches applying etelcalcetide to LVH patients undergoing chronic hemodialysis. Given the known association between secondary hyperparathyroidism, cardiovascular abnormalities, and LVH in dialysis patients, one of ordinary skill in the art would reasonably have expected that suppressing PTH and FGF23 using etelcalcetide could provide therapeutic benefit for LVH related cardiovascular endpoints.
Applying a known PTH and FGF23-suppressing agent to a cardiovascular manifestation associated with SHPT in dialysis patients represents the predictable use of prior art elements according to their established functions (see MPEP 2143). Applicant has not provided persuasive evidence demonstrating that the claimed therapeutic approach was uniquely unpredictable or contrary to the expectations of those skilled in the art. Moreover, attorney argument cannot substitute for objective evidence (see MPEP 716.01(c)). Applicant has not submitted comparative data, experimental evidence, or expert declaration evidence demonstrating that the claimed LVH related outcomes would not reasonably results for the prior art methods.
Furthermore, Applicants reliance on OSI pharmaceuticals, LLC v. Apotex Inc is not persuasive because the factual circumstances are materially distinguishable from the present case. In OSI pharmaceuticals, LLC v. Apotex Inc, the cited references disclosed only generalized exploratory clinical investigations in a highly unpredictable oncology context without meaningful evidence connecting the claimed therapy to clinical efficacy. In contrast, the present case involves a known therapeutic agent (etelcalcetide), a known clinically active dosing regimen, a known dialysis patient population, known biological activity affecting PTH and associated pathways and a specifically designed LVH treatment protocol directed to the same disease state recited in the claims. Unlike the cited case law, Eidman teaches clinically active etelcalcetide dosing in the same dialysis patient population recited in the instant claims, including the same administration route and dosing frequency relied upon by ClinicalTrials. Accordingly, the cited references provide a concrete therapeutic rationale and reasonable expectation that administration of etelcalcetide could beneficially impact LVH associated cardiovascular endpoints.
Unlike the cited case law, the prior art here provides a concrete therapeutic rationale linking etelcalcetide administration to cardiovascular endpoints in dialysis patients. Therefore, the references collectively provide a reasonable expectation of success.
Regarding Applicant’s arguments that ClinicalTrials provides no efficacy results, applicants argument is unpersuasive because actual reduction to practice or completed clinical data are not required to support a prima facie case of obviousness. A claimed invention may be obvious where the prior art suggests the claimed method and provides a reasonable expectation of success, even if results are not available. ClinicalTrials provides the therapeutic protocol and target indication, while Eidman provides evidence that the claimed dosing regimen was pharmacologically effective and clinically tolerated in the same general patient population. The absence of completed efficacy data in ClinicalTrials does not negate the motivation to combine or the reasonable expectation of success arising from the combining teachings of the references. The combination of ClinicalTrials and Eidman therefore represents no more than the application of a known clinically active treatment regimen to closely related therapeutic indication in the same patient population.
With respect to Applicant’s argument that one ordinary skill in the art would not have expected etelcalcetide to treat LVH, the Examiner respectfully disagrees. ClinicalTrials itself evidences that investigators in the field considered etelcalcetide suitable for investigation as a treatment for LVH in dialysis patients. Furthermore, Eidman teaches clinically significant suppression of PTH using etelcalcetide in hemodialysis patients. It would have been obvious to apply the known etelcalcetide dosing regimen taught by Eidman to the LVH treatment protocol taught by ClinicalTrials because both references involve the same active agent, the same administration route, the same dialysis population and overlapping therapeutic goals associated with SHPT related cardiovascular pathology. The optimization of dosage and administration parameters constitutes routine optimization of result effective variables (see MPEP 2144.05).
Eidman expressly teaches dose-dependent physiological effects and identifies 5 mg IV administration three time weekly as a clinically active and tolerated dosing regimen. Accordingly, optimization of dosing parameters to achieve desired PTH suppression and associated cardiovascular effects would have constituted routine optimization of a result effective variable.
Applicants further argue that dependent claims recite additional limitations and are therefore separately patentable. Applicant’s argument is not persuasive because the additional limitations recited in the dependent claims are either expressly taught by the references or would have been obvious routine optimizations. More specifically, regarding claims 35-37 and 52-53, ClinicalTrials specifically teaches chronic hemodialysis patients receiving treatment three times weekly for at least three months. Regarding claims 39-40, ClinicalTrials expressly teaches intravenous administration, which is parenteral administration. Regarding claim 42, ClinicalTrials expressly teaches subjects with SHPT. Regarding claims 43-45, Eidman expressly teaches PTH suppression and target PTH ranges associated with etelcalcetide dosing. Therefore, the dependent claim limitations do not patentably distinguish over the combined teachings of ClinicalTrials and Eidman.
Applicants argue the claimed efficacy limitations are not taught by the prior art (claims 41, 44-47, 49 and 51). Applicants arguments have been considered but not found persuasive. The prior art teaches materially identical treatment methods including the same active agent, the same administration route, the same dosing regimen, the same dialysis patient population and the same treatment duration. MPEP 2112 states “"[T]he PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. 102, on ‘prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same." In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977) (footnote and citation omitted). The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (citing Best, 562 F.2d at 1255).” The claimed efficacy outcomes including alleviation of LVH progression, reduction in LVMI, slowing of fibrosis development and achievement of recited PTH levels would inherently result from practicing the prior art method because the claimed methods do not recite materially distinct process steps from those taught by ClinicalTrials in view of Eidman. ClinicalTrials and Eidman collectively disclose substantially identical treatment conditions, including administration of the same active compound to the same dialysis patient population using the same administration route, dosing frequency, and treatment duration recited in the instant claims. Accordingly, the burden shifts to Applicant to demonstrate that the claimed therapeutic outcomes would not naturally result from practicing the prior art methods.
Applicant has not provided persuasive evidence demonstrating that the claimed outcomes would not inherently arise from the disclosed treatment protocol With respect to the recite “median of about 6.7 g/m2” limitation, Applicant has not established that the claimed statistical outcome reflects a patentably distinct process rather than an inherent property or natural result of administering the prior art protocol to the disclosed patient population.
The recited median reduction merely characterizes the observed patient response resulting from administration of substantially identical prior art treatment methods to substantially identical patient populations and does not reflect a materially distinct treatment step absent from the cited references. Accordingly, the rejection is maintained.
New-Claim Objection
Claim 44 is objected to for the following informality: a space should be placed between blood and parathyroid in line 2.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
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