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
The amendment dated 23 January 2026, in which claims 1, 4, 5, 13, 16, 19 have been amended, and claims 2-3 have been cancelled, is acknowledged.
Claims 1, 4-22 are pending in the instant application.
Claims 9, 12-15, 17 are withdrawn, as being drawn to a non-elected species.
Claims 1, 4-8, 10, 11, 16, 18-22 are examined herein.
Response to arguments of 23 January 2026
In view of Applicant’s amendment of 23 January 2026, all the rejections to claims 2-3 are herein withdrawn. Claims 2, 3 have been cancelled.
In view of Applicant’s amendment of 23 January 2026, the objection to claims 9, 12-15, 17 is herein withdrawn. The status indicators have been corrected.
In view of Applicant’s amendment of 23 January 2026, the objection to claim 1 is herein withdrawn. Applicant has amended claim 1 to recite treating a patient.
In view of Applicant’s amendment of 23 January 2026, the rejection of claims 1-8, 10, 11, 16, 18-22 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. Applicant has clarified the language of claims 1, 3, 4, 6, 19, by indicating the standard or threshold used.
In view of Applicant’s amendment of 23 January 2026, the rejection of claim under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. Claim 5 has been amended to recite above normal RVSP.
In view of Applicant’s amendment of 23 January 2026, the rejection of claim 16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. Applicant has deleted broad/narrow recitation from claim 16.
In view of Applicant’s amendment of 23 January 2026, the rejection of claim 19 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. Applicant has deleted the recitation “such as” from claim 19.
In view of Applicant’s amendment of 23 January 2026, the rejection of claims 1, 7, 8, 10, 11, 18 under 35 U.S.C. 102(a)(1) over Garson, as evidenced by Pollizzotti, is herein withdrawn. A new/modified rejection is made below, based on Applicant’s amendment of 23 January 2026.
Applicant’s arguments (Remarks of 23 January 2026, pages 6-7) against the rejection of claims 1-8, 10, 11, 16, 18-22 1, 4-8, 10, 11, 16, 18-22 under 35 U.S.C. 103 over Garson, in view of Mollova and Pollizzotti, have been considered.
Applicant argues that Garson teaches away from the claimed invention. Applicant argues (page 6) that Garson teaches that treatment with propranolol in a younger patient population (e.g. within the claimed age range of six months or less) was not effective, stating that "[p]atients in whom propranolol therapy was successful were significantly older when treatment with the drug began" (Garson, Abstract and pg. 1099). Applicant argues that Garson teaches that treatment improved patients when drug administration started at a mean age of 11 months (e.g., nearly two times as old as the claimed patient population), with only a small standard error (1.3 months). In contrast, Garson teaches that in patients for which drug administration started at a mean age of 6.1 months, the "condition did not improve". Applicant argues that one of ordinary skill in the art, viewing the teaching of Garson as a whole, would not consider administering a beta blocker to a patient of such a young age.
This argument is not persuasive. Garson teaches (Figure 2, Age at the beginning of propranolol therapy, under Success) that several patients less than 6 months old were successfully treated with propranolol. Garson’s calculations of a mean age per group (which is a statistical parameter) is not relevant for the instant claims; rather, success in treating one patient less than 6 months old is enough to support a teaching of propranolol being effective to treat such infants with tetralogy of Fallot, as in instant claims.
Further, Garson teaches (page 1099, last two paragraphs, page 110, right column) that the dose of propranolol administered was more important than the age of patients: treatment was successful in each patient who received a total dose of more than 2.0 mg/kg per day propranolol (page 1099, right column, last two paragraphs). In an age group of 2 months to 6 months, which are patients of the instant claims, treated with improvement, compared to a group of 2 to 12 months old treated without improvement, the youngest patients in whom the drug was successful received a significantly larger mean dose (2.9 +/- 0.5 mg/kg/day) than that of the patients in which the drug was unsuccessful (1.2 +/- 0.2 mg/kg/day). Garson concludes (page 1100, right column) that propranolol was effective in younger patients as long as the dose was adequate.
Applicant further argues (page 7) that, even if one of ordinary skill in the art would administer a beta blocker to a younger patient population based on Garson, the skilled artisan would not expect the significant improvements seen with the claimed treatment, as set forth in Example 1 in the present application. Applicant provides post-filing evidence (Abstract, published in the journal Circulation in November 2025) describing a clinical experiment in human infants with tetralogy of Fallot (ToF), where the patients were less than six months of age. A significant amount of new cardiomyocytes were generated, and a decreased amount of binucleated cardiomyocytes (e.g., increased cell division) was seen. Garson does not disclose or suggest such effects in such a young patient population. Indeed, Garson does not describe any particular change in patients receiving a beta blocker, other than the patients in which treatment was successful experienced fewer hypoxemic spells (Garson expressly discloses there was no change in anatomy based on the treatment, see Abstract), thus such effects could not be contemplated from the disclosure of Garson. Accordingly, the claims define over Garson in view of Mollova and Pollizzotti. Withdrawal of the rejections is therefore respectfully requested.
This argument is not persuasive. The argument related to the age in the patients of Garson has been addressed above. Further, the person of ordinary skill in the art would have been motivated to measure cardiomyocyte endowment in a 2-month old patient with tetralogy of Fallot treated with propranolol in the method of Garson, because Pollizzotti teaches that the presence of heart disease influences the rate of cardiomyocyte proliferation and pediatric patients with heart disease show decreased cardiomyocyte cell cycle activity. The person of ordinary skill in the art would have measured cardiomyocyte endowment in patient with tetralogy of Fallot, with the expectation that CHD in tetralogy of Fallot is associated with lower than normal cardiomyocyte endowment.
Further, the person of ordinary skill in the art would have been motivated to determine the proportion of binucleated cardiomyocytes in the heart tissue, prior to and during treatment with propranolol, and to determine heart tissue growth in said patient, because Mollova teaches the methodology used to monitor cardiomyocyte proliferation, and determining % of mono-, di- , multinucleated cardiomyocytes, cardiomyocyte proliferation being important for regeneration and postnatal heart growth in young humans/infants.
Even though the references cited do not specifically teach that the administering propranolol to a 2 month-old infant with tetralogy of Fallot increases cardiomyocyte endowment and improves heart function, as in instant claims, the ability to increase cardiomyocyte endowment and to improve heart function, in a patient upon administration, are inherent properties of propranolol. In the instant case, increasing cardiomyocyte endowment and improving heart function in the patient, are inherently associated with treatment of infant patients with tetralogy of Fallot by administering nonspecific beta-blocker propranolol.
Since Garson teaches administration of the very same therapeutic agent, propranolol, to the very same patient population, patients suffering tetralogy of Fallot, to treat said patients, said therapeutic agent, upon administration, will elicit the same effect on the cardiomyocyte endowment and heart function in said patients.
For all these reasons, the rejection of the claims is herein maintained, and a modified rejection is made below, based on Applicant’s amendment of 23 January 2026.
The claims have been examined to the extent they read on the elected species: patients with tetralogy of Fallot as the congenital heart defect, to be treated; propranolol as the therapeutic agent administered in the method of treatment; and neuregulin as the additional therapeutic agent administered in the method of treatment, and the following rejections are made below, based on Applicant’s amendment of 23 January 2026.
Claim Rejections- 35 USC 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner 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 interpretation: the recitation “normal RVSP” in claim 5 is interpreted to be, based on [0104] Specification, 15 mmHg to 30 mm Hg for pre-term and infants less than 6 months old.
Claims 1, 4-8, 10, 11, 16, 18-22 are rejected under 35 U.S.C. 103 as being unpatentable over Garson et al. et al. (The American Journal of Cardiology 1981, 47, 1098-1104, cited in IDS), in view of Mollova et al. (PNAS 2013, 110 (4), 1446-1451, cited in IDS) and Pollizzotti et al. (Science Translational Medicine, Pediatric Cardiology 2015, 7 (281), 281ra45, p. 1-13, cited in PTO-892 of 24 September 2025).
Garson teaches administration of nonselective beta-blocker propranolol, as in instant claims 1, 8, 10, to infants (human patients, as in instant claim 18) with tetralogy of Fallot, as in instant claim 11.
Garson teaches (page 1099, right column, first paragraph under Results) that the age of the patients ranged from 2 to 30 months when treatment with propranolol was started, which is consistent with at least one patient being a 2 month-old infant, which is within the age range for the patient population in the instant claims.
Garson teaches (Figure 2, age at the beginning of propranolol therapy) that several patients in whom propranolol therapy was successful were less than 6 months old, as in the instant claims.
Garson teaches (page 1099, left column, last paragraph) that cardiac catheterization was performed in each patient before administration of propranolol, and the cineangiocardiograms were used to calculate right ventricular end diastolic volume index, right ventricular ejection fraction index, INFUNDIB/Ao ratio, Figure 4), which are tools to monitor right heart function. The cineangiocardiogram, part of heart catheterization, which is the golden standard for measuring RVSP, as in instant claim 5, and intracardiac pressures.
Garson is silent regarding the patient being cyanotic, which satisfies the limitation in instant claim 7.
While Garson does not teach that patients having congenital heart defect associated with tetralogy of Fallot have reduced cardiomyocyte endowment resulting from heart cell division failure, compared to normal (patients without CHD), Pollizzotti teaches (page 1, right column, first paragraph) that, although endogenous cardiomyocyte proliferation can be detected in humans without heart disease up to 20 years of age, the presence of heart disease influences the rate of cardiomyocyte proliferation. Pollizzotti teaches (Figure 6) that pediatric patients with heart disease show decreased cardiomyocyte cell cycle activity.
Mollova et al. (PNAS 2013, 110 (4), 1446-1451, cited in IDS) teaches that cardiomyocyte proliferation contributes to heart growth in young humans.
Mollova teaches the methodology used to monitor cardiomyocyte proliferation, which is important for regeneration and postnatal heart growth in young humans/infants. Mollova teaches image-based assays used to determine the extent and timing of cardiomyocyte cell cycling, proliferation, and to relate the activity of these mechanisms to the growth of human heart.
Mollova teaches determining % of binucleated cardiomyocytes in heart tissue, detecting cardiomyocyte cytokinesis in human heart, detecting evidence for cardiomyocyte proliferation (Fig. 5).
Pollizzotti (Science Translational Medicine, Pediatric Cardiology 2015, 7 (281), 281ra45, p. 1-13) teaches (Abstract) that administration of the recombinant growth factor neuregulin (which is Applicant’s elected species of a therapeutic agent of instant claims 21, 22), induced cardiomyocyte proliferation in myocardium from infants with heart disease who were less than 6 months of age.
Pollizzotti teaches (page 1, left column, first paragraph) that corrective heart surgery, as in instant claim 16, enables young patients to survive congenital heart disease (CHD).
Pollizzotti teaches (page 1, left column, first paragraph) that patients with CHD are at risk at developing heart failure, as in instant claim 19, and stimulation of cardiomyocyte regeneration improved myocardial function and structure (Abstract, Figure 2).
It would have been obvious to a person of ordinary skill in the art to combine the teachings of Garson, Mollova and Pollizzotti to arrive at the instant invention. The person of ordinary skill in the art would have been motivated to measure cardiomyocyte endowment in a 2-month old patient with tetralogy of Fallot, because Pollizzotti teaches that the presence of heart disease influences the rate of cardiomyocyte proliferation and pediatric patients with heart disease show decreased cardiomyocyte cell cycle activity. The person of ordinary skill in the art would have measured cardiomyocyte endowment in patient with tetralogy of Fallot, with the expectation that CHD in tetralogy of Fallot is associated with lower than normal cardiomyocyte endowment.
Further, the person of ordinary skill in the art would have been motivated to determine the proportion of binucleated cardiomyocytes in the heart tissue, prior to and during treatment with propranolol, and to determine heart tissue growth in said patient, because Mollova teaches the methodology used to monitor cardiomyocyte proliferation, and determining % of mono-, di- , multinucleated cardiomyocytes, cardiomyocyte proliferation being important for regeneration and postnatal heart growth in young humans/infants.
Even though the references cited do not specifically teach that the administering propranolol to a 2 month-old infant with tetralogy of Fallot increases cardiomyocyte endowment and improves heart function, as in instant claims, the ability to increase cardiomyocyte endowment and to improve heart function, in a patient upon administration, are inherent properties of propranolol. In the instant case, increasing cardiomyocyte endowment and improving heart function in the patient, are inherently associated with treatment of infant patients with tetralogy of Fallot by administering nonspecific beta-blocker propranolol.
Since Garson teaches administration of the very same therapeutic agent, propranolol, to the very same patient population, patients suffering tetralogy of Fallot, to treat said patients, said therapeutic agent, upon administration, will elicit the same effect on the cardiomyocyte endowment and heart function in said patients.
Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. See MPEP 2145.II.
Regarding claims 20-22, the person of ordinary skill in the art would have been motivated to administer neuregulin to an infant with tetralogy of Fallot, because Pollizzotti teaches administration of the recombinant growth factor neuregulin induced cardiomyocyte proliferation in myocardium from infants with heart disease who were less than 6 months of age, and stimulation of cardiomyocyte regeneration improved myocardial function and structure and reduces the risk of developing heart failure in patients with CHD.
As such, claims 1, 4-8, 10, 11, 16, 18-22 are rejected as prima facie obvious.
Conclusion
Claims 1, 4-8, 10, 11, 16, 18-22 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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