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
Claims 1-4, 7-9, 11-15, 18-24 and 26 are pending in the application. Claims 7-9, 11-15, 18-24 and 26 are rejected. Claims 1-4 are withdrawn from further consideration.
Election/Restrictions
Applicant’s election without traverse of the species of atenolol and mirabegron to prosecute the invention of Group II, claims 7-9, 11-15, 18-24 and 26, in the reply filed on June 23rd, 2026 is acknowledged.
As per MPEP 803.02, the examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species are not allowable. MPEP 803.02 states:
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. […]
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration. […]
If on examination the elected species is found to be anticipated or rendered obvious by prior art, the Markush claim and claims to the elected species will be rejected, and claims to the nonelected species will be held withdrawn from further consideration.
As the elected species has been found not allowable, the Markush-type claims have been rejected and claims to the nonelected invention held withdrawn from further consideration. Claims 7-9, 11-15, 18-24 and 26have been examined to the extent that they are readable on the elected embodiment. Since the elected species are not allowable, subject matter not embraced by the elected embodiment is therefore withdrawn from further consideration.
Art applicable to additional species was discovered incidental to the search of the elected species and is addressed below under 35 USC 103, in particular where the ADRB1 antagonist is nadolol and ADRB3 agonist is BRL37344.
Claims 1-4 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 23rd, 2026.
Information Disclosure Statement
The Examiner has considered the Information Disclosure Statement(s) filed on February 26th, 2024 and August 13th, 2026.
Claim Rejections - 35 USC § 112(b)
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 9 and 21-23 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 9 recites the limitation "the composition" in line 2. There is insufficient antecedent basis for this limitation in the claim. Parent claim 7 does not recite or refer to a composition and it is unclear if claim 9 is attempting to recite or require that both the ADRB1 agonist and ADRB3 agonist are contained in the same composition or if “the composition” is only referring to one of the two agents.
Claim 21 recites the limitation "the least one untoward effect on the cardiovascular system resulting from ADRB3 agonist administration in a subject in need thereof" in lines 1-3. There is insufficient antecedent basis for this limitation in the claim. Parent claim 14 does not recite or require that the untoward effect occur in “a subject in need thereof” but rather “a subject”. It is unclear if the comparison in claim 21 must occur in a certain patient population, and is so, which one.
Claim 22 recites the limitation "the least one untoward effect on the cardiovascular system resulting from ADRB3 agonist administration in a subject in need thereof" in lines 1-3. There is insufficient antecedent basis for this limitation in the claim. Parent claim 14 does not recite or require that the untoward effect occur in “a subject in need thereof” but rather “a subject”. It is unclear if the comparison in claim 22 must occur in a certain patient population, and is so, which one.
Claim 23 recites the limitation "the least one untoward effect on the cardiovascular system resulting from ADRB3 agonist administration in a subject in need thereof" in lines 1-3. There is insufficient antecedent basis for this limitation in the claim. Parent claim 14 does not recite or require that the untoward effect occur in “a subject in need thereof” but rather “a subject”. It is unclear if the comparison in claim 23 must occur in a certain patient population, and is so, which one.
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.
Claim(s) 7-9, 11-15, 18-24 and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent PGPub No. 2008/0249176 A1 by Rasmussen et al. in view of Mukaida et al. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2019, 316, R666-R677.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Rasmussen et al. teach the following general methods on page 12 including treatment of heart failure:
3. A method for the treatment of an individual suffering from or susceptable to heart failure or myocardial hypertrophy, said method comprising administering a therapeutically effective amount of one or more β3 adrenoceptor agonists to said individual.
4. The method according to claim 3 wherein the individual is an individual having one or more clinical symptoms of heart failure or myocardial hypertrophy.
The prior art further teaches dependent claims 6 and 7 reciting the particular use of BRL37344:
6. The method according to claim 3 wherein the β3 adrenoceptor agonist is selected from the group consisting of BRL37344, BRL 35135, BRL 26830, BRL 26830A, BRL 35113, ZD7114, CGP12177, CGP 12177A, CGP-20712A, CL316243, ICI07114, ICI215001, ICI 201651, BRL35135A, BRL28410, N-5984, (R)--N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(- 4-trifluoro-methylphenyl)thiazol-2-yl]benzenesulfonamide (L-796568), (R)--N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-oc- tylthiazol-2-yl)-5-indolinesulfonamide (L-755507), L-770,644, L-766,892, L-757,793, L-796568, LY-377604, Ro 40-2148, SB-220646, SB-226552, SB-251023, SB-262552, SR 58306, SR 58375, SR 58339, SR 58611, SR 58611A, SR 59119A, GR-265261-X, AD-9677, and agonists of the series 2-(3-indolyl) alkylamino-1-(3-chlorophenyl)ethanols.
7. The method according to claim 3 wherein the β3 adrenoceptor agonist is BRL37344.
The prior art further teaches combinations including the following as claims 9 and 10 on page 12:
9. The method according to claim 3 further comprising administering one or more β blockers to said individual.
10. The method according to claim 9 wherein the β blocker is nadolol.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art generally teaches administration of an ADRB1 antagonist, including nadolol as recited in instant claims 12 and 15, in combination with an ADRB3 agonist, including BRL37344 as recited in instant claims 13 and 15. The prior art does teach an explicit embodiment where the noted combination was administered for treating and/or preventing a metabolic disorder in a subject in need thereof as recited in instant claim 7. Additional limitations are addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2141.02)
Regarding the scope of subjects, Rasmussen et al. teach the following on page 1:
[0003] In the Western world the prevalence of symptomatic heart failure is approximately 2%. In the United States ~5 million people are treated for it and it is estimated that 50-60 million Americans (~20%) are at risk of developing heart failure (Gheorghiade et al., 2003). This group includes people suffering from one or more of the leading causes for development of heart failure, i.e. coronary artery disease, diabetes, hypertension or valvular heart disease.
Accordingly, a person having ordinary skill in the art would expect that patients being treated for heart failure would include both subjects having diabetes and subjects suspected of having diabetes. Rasmussen et al. additionally teach on page 5:
[0081] β3 adrenoceptors are expressed in many tissues, including the heart, and are present in many species including humans. Prior to the present invention the primary clinical and pharmacological interest in β3 adrenoceptors has been related to a potential role of β3 adrenoceptors agonists ("activators") in the treatment of obesity and type II diabetes mellitus, based on findings in rodents that β3 adrenoceptors agonists induce an increase in metabolic rate, a lipolytic effect and an increased insulin sensitivity.
Furthermore, Mukaida et al. teach that BRL37344 promotes glucose uptake including the following on page R676:
We have shown that BRL37344 increases glucose uptake into skeletal muscle by activation of 2-ARs in vitro, ex vivo, and in vivo. This involves increased translocation of GLUT4 to the cell surface by a mechanism involving activation of mTORC2 but utilizing a signaling pathway not involving Akt, clearly distinguishing the pathway from that promoted by insulin. Importantly, BRL37344 achieves this with minimal increases in cAMP and without recruiting-arrestin to the receptor or receptor desensitization. The ability of BRL37344 to promote glucose uptake utilizing pathways other than those utilized by insulin that are desensitized in T2D may offer therapeutic opportunities. The results presented here suggest that targeting the 2-AR with agonists possessing these beneficial characteristics may provide a novel approach to the treatment of T2D.
Accordingly, a person having ordinary skill in the art would have expected that a combination containing BRL37344 would be useful in treating the subjects having or suspected to have type 2 diabetes in need of treatment for heart failure within the generic scope of Rasmussen et al.
Regarding instant claim 8, the discussion above applies at least to type 2 diabetes mellitus and Mukaida et al. teach positive benefits of BRL37344 on glucose uptake relative to claim 9. Regardless, MPEP 2145(II) notes: ‘ "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)’. In this situation, the prior art suggests administration of the same claimed combination to a patient population instantly recited. Furthermore, the instant claim 9 places no limitation on how much of an effect must occur. The prior art generally teaches dosages can be determined by routine experimentation including the following on pages 7 and 8 of Rasmussen et al.:
[0114] One skilled in the art would be able, by routine experimentation, to determine an effective, non-toxic amount of the β3 adrenoceptor agonist, and other agents where appropriate, which would be required to treat the condition.
[0115] Generally, an effective dosage is expected to be in the range of about 0.00001 mg to about 1000 mg per kg body weight per 24 hours; typically in the range of about 0.0001 mg to about 1000 mg per kg body weight per 24 hours; typically, about 0.001 mg to about 750 mg per kg body weight per 24 hours; about 0.01 mg to about 500 mg per kg body weight per 24 hours; about 0.1 mg to about 500 mg per kg body weight per 24 hours; about 0.1 mg to about 250 mg per kg body weight per 24 hours; about 1.0 mg to about 250 mg per kg body weight per 24 hours. More typically, an effective dose range is expected to be in the range about 1.0 mg to about 200 mg per kg body weight per 24 hours; about 1.0 mg to about 100 mg per kg body weight per 24 hours; about 1.0 mg to about 50 mg per kg body weight per 24 hours; about 11.0 mg to about 25 mg per kg body weight per 24 hours; about 5.0 mg to about 50 mg per kg body weight per 24 hours; about 5.0 mg to about 20 mg per kg body weight per 24 hours; about 5.0 mg to about 15 mg per kg body weight per 24 hours.
While the narrowed limitations of the specification are not imported to the instant claims, the ranges above largely overlap with dosages recited in the instant specification when applied to humans that can be applied in the instant methods, such as on page 27 (paragraph [0097]) of the instant specification. The same rationale would apply to instant claim 26 that recites an addition effect with no requirement that the difference must be of any particular degree or clinical relevance.
Regarding instant claim 11, this claim generally encompasses administering the same combination discussed above to the same subject population. Dependent claims 12 and 13 both embrace nadolol and BRL-37344, respectively, dependent claim 15 similarly recited both noted compounds, and dependent claim 24 recites the subject has or is suspected of having a metabolic disorder. The preamble of claim 11 recites “for reducing the dosage of a beta-3 adrenergic receptor (ADRB3) agonist” but where the claim does not require that the subject ever be administered a higher dosage of ADRB3 agonist. The claim would still embrace methods of treating where an optimum dosage of ADRB3 agonist and ADRB1 antagonist are developed in tandem. The fact that the same dosage of ADRB3 agonist would produce a different effect in the absence of ADRB1 antagonist largely appears to be a result consistent with MPEP 2145 especially since a person having ordinary skill in the art would not need to be aware of the effect of an ADRB3 agonist administered by itself in order to optimize the combination taught by the prior art. The same rationale in view of MPEP 2145 applies to the effects recited in claims 14, 21-23 and 26 that either address effects of the ADRB3 agonist alone or effects requiring no minimum or clinical significance.
Regarding instant claims 18-20, Claim 12 of Rasmussen et al. recites (page 12):
12. The method according to claim 9 wherein the β blocker is administered to said individual prior to, simultaneously with or subsequent to administration of the one or more β3 adrenoceptor agonists.
The instant claims would appear to encompass, for instance, a subject taking one composition orally followed by the second in quick succession or swallowing both oral compositions at the same time (where paragraph [0121] of Rasmussen et al. teaches oral administration). At least since Rasmussen et al. teach simultaneous administration, the instantly claimed approaches would appear to merely represent variations dependent upon a subject’s ability or preference to swallow multiple compositions at the same time.
Claim(s) 7-9, 11-15, 18-24 and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent PGPub No. 2008/0249176 A1 by Rasmussen et al. in view of Mukaida et al. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2019, 316, R666-R677, as applied to claims 7-9, 11-15, 18-24 and 26 above, and in further view of U.S. Patent PGPub No. 2011/0081426 A1 by Rao et al.
The rejection under 35 USC 103 above addresses a combination of BRL-37344 and nadolol whereas the instant elected species correspond to a mixture of atenolol and mirabegron. In paragraphs [0094] and [0095] on page 6, Rasmussen et al. teach atenolol as an example of β1 and/or β2-adrenoreceptor antagonists within the same list as nadolol. At least in the interest of determining optimum combinations, a person having ordinary skill in the art would have been motivated to test the permutations using atenolol in place of nadolol. Regarding mirabegron, Rasmussen et al. teach on page 6:
[0088] It will be appreciated that the method of the invention contemplates the use of any suitable β3 adrenoceptor agonist and that specific groups and compounds are stated herein by way of exemplification and not by way of limitation.
Furthermore, a person having ordinary skill in the art would have been familiar with mirabegron as a β3 adrenoceptor agonist. For instance, Rao et al. teach on page 1:
[0003] Mirabegron (YM-178, CAS # 223673-61-8), 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thia- zoleacetamide, is a beta-3-adrenoreceptor agonist. Mirabegron is currently under investigation for the treatment of overactive bladder, irritable bowel syndrome, type 2 diabetes, and obesity (US 2009093529; US 2008214633; and Takasu et al., J. Pharmacol. Exp. Ther. 2007, 321(2), 642-647).
Furthermore, Rao et al. teach that the deuterated versions thereof can be used in combination in paragraph [0092] as follows:
Examples of anti-hypertensive agents include […]; b-adrenergic receptor blockers, for example acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol or timolol; […].
Rao et al. teach possible combinations with both nadolol and atenolol. Rao et al. further teach methods of treating type 2 diabetes in, for instance, claim 18 on page 42. Accordingly, a person having ordinary skill in the art would have recognized mirabegron as a known β3 adrenoceptor agonist and would have reasonably expected a combination of mirabegron and atenolol to be useful within the generic method of Rasmussen et al. and with particular benefit to patients having or suspected of having type 2 diabetes in view of Rao et al. The limitations of claims 7 and 11 and the various instant dependent claims are rejected as obvious for the same rationales as under the first rejection under 35 USC 103.
Regarding data found in the instant specification, Applicant discloses results based on the following groups:
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Figure 6c shoes that mirabegron + ateneolol results in a lower MBP than mirabegron alone. MPEP 716.02(d) states:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)
Even if the results were considered evidence of unexpected results, they would not be commensurate in scope with the subject matter found to be obvious at least since the instant claims embrace additional ADRB1 antagonist/ADRB3 agonist combinations besides the one tested (i.e. the combination cited in the first rejection under 35 USC 103) and since the instant claims do not place any limitation of the ratio between them or dosage being applied.
Conclusion
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/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626
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