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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on August 5, 2026 has been entered.
Detailed Action
This office action is a response to applicant’s communication submitted August 5, 2026, wherein claims 108 and 114 are amended and claim 115 is canceled. This application is a continuation of US application 17/184746, now US patent 11909355, filed February 25, 2021, which is a continuation of US application 16/812745, now US patent 10973836, filed March 9, 2020, which claims benefit of provisional applications 62/985407, filed March 5, 2020, 62/969181, filed February 3, 2020, 62/960756, filed January 14, 2020, 62/946625, filed December 11, 2019, 62/930673, filed November 5, 2019, and 62/893849, filed August 30, 2019.
Claims 108-111, 114, 117, 118, and 120-124 are pending in this application.
Claims 108-111, 114, 117, 118, and 120-124 as amended are examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, submitted August 5, 2026, with respect to the rejection of claims 114 and 115 under 35 USC 112(d) for failing to further limit the base claim, has been fully considered and found to be persuasive to remove the rejection as the claim 114 has been amended to narrow the scope of outcomes specifically to delaying the onset of diabetes, and claim 115 is canceled. Therefore the rejection is withdrawn.
The following rejections of record in the previous action are maintained:
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 108-111, 114, 117, 118, 120-122, and 124 are rejected under 35 U.S.C. 103 as being unpatentable over Bindra et al. (US pre-grant publication 2014/0243262, of record in previous action) in view of Preiss et al. (Reference of record in previous action)
Independent claim 108 is directed to a method of delaying the onset of diabetes in a patient suffering from heart failure with reduced ejection fraction, (HFrEF) comprising administering a therapeutically effective amount of dapagliflozin to the patient, wherein the patient does not have type 2 diabetes at the time of initiating therapy.
Bindra et al. discloses oral pharmaceutical formulations comprising dapagliflozin. (pp. 1-2 paragraph 8) These pharmaceutical compositions can be administered to a subject in order to delay the onset or progression of type 2 diabetes or other SGLT2-related conditions such as metabolic syndrome. (p. 3 paragraphs 22-24) Bindra et al. differs from the claimed method in that it does not specifically describe delaying the onset or progression of type 2 diabetes in a patient suffering from heart failure with reduced ejection fraction.
However, Preiss et al. discloses a study of the development of diabetes in patients suffering from chronic heart failure. (p. 916 left column first paragraph) The patients specifically are described as having a left ventricular ejection fraction of less than 0.40, indicating HFrEF. (p. 916 left column second paragraph) Of these patients, 6.7% developed diabetes during the study period, coming to 27.8 per 1000 patient-years. (p. 917 middle column second paragraph) Preiss et al. further suggests identifying high-risk individuals within the population of CHF patients and applying treatment to reduce progression to diabetes.
It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to administer the dapagliflozin-containing pharmaceutical dosage unit described by Bindra et al. to a nondiabetic patient suffering from HFrEF, in order to reduce the development of diabetes in said patient. One of ordinary skill in the art would have seen the disclosure of Preiss et al. as specifically suggesting looking for ways to reduce progression to diabetes in this patient population and would have seen Bindra’s therapeutic agent as being useful for this purpose based on the disclosed indications described by Bindra.
Regarding claim 109, Bindra et al. suggests administering the dapagliflozin or dapagliflozin propylene glycol hydrate in a dosage of about 0.5-100 mg in single or divided doses. (p. 11 paragraph 123) Bindra et al. further exemplifies a 10 mg tablet as a dosage form for dapagliflozin. (p. 18 example 8) One of ordinary skill in the art would have therefore considered the dosage of dapagliflozin to be a result-effective variable, and would have found it to be obvious to determine the optimal dosage for this compound, for example at the value of 10 mg exemplified in the disclosure, rendering claim 109 obvious.
Regarding claims 110 and 111, A1c was seen to be associated with the development of diabetes, and therefore to be a risk factor to be taken into consideration. (p. 197 left column first paragraph) IT would have been obvious to one of ordinary skill in the art at the time of the invention to specifically identify the patient’s A1c level as part of the process of determining their risk of progression to diabetes. In particular this is especially true for claim 111, as an elevated A1c level would indicate increased risk of progression.
Regarding independent claim 117, this claim is directed to a method of preventing and/or delaying a fatal cardiovascular event in a patient with HFrEF who does not have type 2 diabetes, comprising administering dapagliflozin to the patient. This claim differs from claim 108 in that the condition being prevented or delayed is a fatal cardiovascular even rather than development of diabetes, however, in addition to the teachings of Bindra and Preiss described above, Preiss et al. describes diabetes as being a predictor of cardiovascular morbidity and mortality in patients with heart failure. (p. 915 right column first paragraph) Therefore it stands to reason that delaying or preventing the development of diabetes is reasonably considered to additionally accomplish delay or prevention of a fatal cardiovascular event in a portion of patients suffering from HFrEF. Therefore it would have been obvious to one of ordinary skill in the art to administer dapagliflozin to this patient population for the purpose of preventing or delaying cardiovascular death, according to claim 117 and also dependent claim 119.
Regarding claim 118, this claim recites the same dosage as claim 109 and is obvious for the same reasons given with respect to claim 109, in view of the fact that as discussed under 35 USC 112(d) this claim does not actually limit the scope of base claim 117.
Regarding claims 120-121, while the cited references do not specifically describe the claimed time ranges, Preiss et al. discloses that patients were followed for a median of 2.8 years. (p. 917 center column second paragraph) This indicates that delays of up to 24 months (2 years) are reasonably possible if the development of diabetes is prevented.
Regarding claim 122, p. 916 table 1 of Preiss discloses that about 50% of patients being studied had already suffered a myocardial infarction, indicating that this is a common finding in patients with HFrEF. Given the desirability of preventing diabetes and further cardiovascular events in these patients, it would have been obvious to one of ordinary skill in the art at the time of the invention to administer therapy as quickly as possible, for example immediately after such an event. Therefore the further limitation described by claim 122 is obvious.
Regarding claim 124, this claim requires that the method reduces worsening of heart failure symptoms in the patient during a period of 12-36 months. As discussed previously, Preiss discloses that diabetes is associated with wore outcomes in heart failure. (p. 919 left column last paragraph) Furthermore the study described by Preiss observed the development of new diabetes cases among the study population over a median follow up of 2.8 years, or 33.6 months. (p. 917 center column second paragraph) Since the development of diabetes would be expected to lead to a worsening of heart failure symptoms, it is reasonable to conclude that a treatment that delays or prevents the incidence of diabetes during this time, such as that described by Bindra, would reduce any worsening of heart failure symptoms during this time that would be attributable to the development or progression of diabetes.
Therefore the invention taken as a whole is prima facie obvious.
Claim 123 is rejected under 35 U.S.C. 103 as being unpatentable over Bindra et al. in view of Preiss et al. as applied to claims 108-111, 114, 117, 118, 120-122, and 124 above, and further in view of Wang et al. (Reference of record in 1/11/2024 PTO-1449)
The disclosures of Bindra and Preiss are discussed above. Bindra in view of Preiss does not specifically describe a process wherein the patient suffers from acute decompensated heart failure. However, Wang et al. discloses that there is a large population of patients with acute decompensated heart failure in need of improved treatment. (p. 401 left column first three paragraphs) Wang et al. further discloses a population of patients having decompensated heart failure and reduced ejection fraction. (p. 401 right column first paragraph and “study designs and study population”) It would have been obvious to one of ordinary skill in the art at the time of the invention to apply the treatment protocol described by Bindra in view of Preiss to patients having acute decompensated heart failure as described by Wang et al. One of ordinary skill in the art would have been motivated to treat this patient population because they are a subset of the broader population of patients having HFrEF described by the primary reference.
Therefore the invention taken as a whole is prima facie obvious.
Response to Arguments
Applicant’s arguments, submitted August 5, 2026, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejections. Applicant makes two separate sets of arguments with respect to the two independent claims 108 and 117.
With respect to claim 108 and its dependent claims, Applicant argues that Bindra does not disclose treatment of patients suffering from heart failure, secondly that Preiss suggests a need to reduce the progression of diabetes in patients with heart failure, rather than delaying the onset of diabetes, and thirdly, that Preiss does not disclose using SGLT2 inhibitors at all and suggests targeting A1c and BMI to delay diabetes progression, factors that Bindra does not specifically suggest as being affected by dapagliflozin.
Concerning to the first argument, this argument does not touch upon the actual reason for combining the two references. While Bindra does not specifically mention hear failure or cardiovascular disease, p. 3 paragraph 23 of Bindra describes “delaying the progression or onset of type II diabetes” as being one therapeutic use of dapagliflozin. This broad scope of patients in need of treatment would then be connected by one of ordinary skill in the art to the suggestion by Preiss (p. 919 middle column first paragraph, p. 920 left column last paragraph) to identify high risk individuals and provide treatment to reduce progression to diabetes. A finding of obviousness does not require that each reference cited identify every element of the claimed invention so long as there is sufficient guidance to suggest incorporating the missing elements. In the present case, this guidance is provided by the open-ended suggestion by Preiss to identify HFrEF patients at high risk for diabetes and apply an appropriate therapy to reduce the risk of diabetes.
With respect to the second argument, this depends on there being a difference between “progression to diabetes” as described by Preiss and “onset of diabetes” as recited in the present claims. This term is not specifically defined in the present specification in a way that would give it some specific meaning that could distinguish it from the prior art or from references to “preventing or delaying the incidence of diabetes” elsewhere the specification. Furthermore p. 3 paragraph 8 of the specification, when listing embodiments of “preventing or delaying the incidence of diabetes” specifically describes a patient with HFrEF and without T2D as being prediabetic, defined as an A1C between 5.7% and 6.5%, and the therapeutic effect as being measured by the time to an A1C measurement of greater than 6.5%. Looking to this definition, there does not seem to be any clear support for the assertion that “onset of diabetes” in the claims and “progression to diabetes” as described in Preiss. Applicant should further note that “progression to diabetes” as described by Preiss and the previous office action refers not to worsening of diabetic symptoms in a patient already meeting the diagnostic criteria for diabetes (as appears to be Applicant’s interpretation) but rather to the development of diabetes in a previously nondiabetic patient having some existing risk factor.
Concerning the third argument, this appears to be an argument that Preiss teaches away from using dapagliflozin to prevent development of diabetes in this patient population, in favor of an angiotensin II receptor blocker or a therapy directed specifically to reduce BMI or A1c.
Firstly, while the CHARM study described by Preiss was in fact originally conceived as a study of the efficacy of the ARB candesartan, the actual focus of this particular article is on the incidence of diabetes in the study population and the development of diabetes in some of the subjects during the study. Preiss never suggest using candesartan to prevent, treat, or delay diabetes. Secondly, while Preiss notes that, in keeping with what is generally known about the incidence of diabetes, BMI and A1C are strong predictors of diabetes risk, and further suggests screening heart failure patients for A1C as a marker of diabetes risk, the reference refers only generally to “steps to reduce this risk [of developing diabetes],” without teaching toward or away from any particular approach. Therefore one of ordinary skill in the art would have seen any therapeutic approach known to be useful for diabetes prevention to be appropriate for use in this patient population.
Regarding claim 117 and its dependent claims, Applicant argues that one of ordinary skill in the art would not have looked to Bindra for use of dapagliflozin in patients suffering from cardiovascular disease because Bindra does not mention heart failure at all. However, for the same reasons discussed previously, Preiss suggests that treatment aimed at reducing diabetes risk in nondiabetic patients having HFrEF and at risk of diabetes would improve clinical outcomes. For the same reasons given above for methods of delaying onset of diabetes, one of ordinary skill in the art would have expected that administering dapagliflozin to a nondiabetic patient having HFrEF and additionally being at risk of diabetes (e.g. having an elevated but nondiabetic A1C) would both prevent or delay the onset of diabetes. Since Preiss states that this would improve clinical outcomes, it would additionally be expected to prevent or delay a fatal cardiovascular event. The fact that the patients in the CHARM study were receiving candesartan as a treatment for heart failure does not suggest that one of ordinary skill in the art would have looked to angiotensin II receptor blockers to mitigate the risk of developing diabetes, with the associated additional risk of cardiovascular death.
Applicant additionally states that claim 117 specifically excludes patient already having diabetes, and a person of ordinary skill in the art would not have looked to Preiss to treat such subjects. However, this is not actually the case, since Preiss is specifically concerned with the development of diabetes in patients who were initially nondiabetic. This patient population falls within the scope of patients who do not have type II diabetes as described in claim 117. Applicant is reminded that, as stated in p. 3 paragraph 8 of the present specification, patients who do not have type II diabetes include those having prediabetes. (i.e. at elevated risk for diabetes, and having elevated A1C)
Finally, Applicant additionally argues that the cited references Inzucchi, Caffrey, and Kaplinski all demonstrate a finding of unexpected results. These references describe the DAPA-HF trial, on which the presently claimed invention is based, as significant both in that it “is the first study to suggest a diabetes prevention effect form an SGLT2 inhibitor,” and that “it is the first study to demonstrate that a single drug may prevent both diabetes and death.”
Regarding the diabetes-preventative effect of SGLT2 inhibitors, while it is possible that DAPA-HF in the first human clinical trial to establish such an effect, this is merely confirmation of what would reasonably be the expected effect. For example, as discussed previously, Bindra already describes a preventative effect on diabetes as expected. Furthermore, looking to the disclosure of Inzucchi et al. referred to by Applicant, diabetes is defined as an A1C of 6.5% or greater. (see p. 587 right column second paragraph, p. 591 left column first paragraph) Among patient who developed diabetes during the trial, a significant majority were prediabetic, as many as 95% based on the criterion used. (p. 588 right column second paragraph) Furthermore it is already known in the art that dapagliflozin can lower elevated A1c in patients at various stages of disease progression (see Zhang et al., included with PTO-892, for example p. 512 table 2, figure 1) and that pharmacotherapy to prevent progression of prediabetes to diabetes can be effective (see McLellan et al., included with PTO-892, pp. 179-181) it is not actually unexpected that prediabetic patients (i.e. having elevated A1C) administered dapagliflozin would experience delay or prevention of the development of clinical diabetes, defined herein as an A1C of 6.5% or above.
Regarding the reduction in cardiovascular mortality, while DAPA-HF may have been the first human clinical trial to observe this effect for dapagliflozin, as disclosed by Savarese et al. (Reference included with PTO-892) the previous clinical trial EMPA-REG OUTCOME demonstrated a similar reduction in mortality using a different SGLT2 inhibitor, empagliflozin. (see p. 1459 figure 1)
Therefore in both cases, the results of the DAPA-HF clinical trial, while significant, serve to confirm what would have been the expected outcome based on previous knowledge in the field of diabetes and SLGT2 inhibition. Such findings do not amount to a finding of unexpected results sufficient to overcome a case of prima facie obviousness.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA OLSON whose telephone number is (571)272-9051. The examiner can normally be reached M-F 6am-3:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Y Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANDREA OLSON/ Primary Examiner, Art Unit 1693 9/3/2026
Prosecution Insights