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 .
Specification
The use of the tradenames in the example embodiments, has been noted in this application on page 3 lines 3 – 13 and page 12 lines 15 - 20. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 13, 16, and 19 are objected to because of the following informalities: a double inclusion of the genus of phosphodiesterase inhibitors in lines 2 and 4 of claims 13, 16, and 19. In all three claims both the genus of “phosphodiesterase inhibitors” as well as its subgenus “phosphodiesterase-5 inhibitors (PDE-5)” are taught. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1 – 3, and 7 – 11 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication US 2010/0099707 A1 to Amer (herein after Amer’707; cited on IDS dated May 21st, 2024) in view of Todd et. al. ((1995), Chronic Administration of the Antidepressants Phenelzine, Despiramine, Clomipramine, or Maprotiline Decreases Binding to 5-Hydroxytryptaminea2A Receptors Without Affecting Benzodiazepine Binding Sites in Rat Brain, Cellular and Molecular Neurobiology, 15, 361 – 370; cited on IDS dated May 21st, 2024).
Regarding claims 1 – 3, and 7 – 11, Amer’707 the use of combined 5-HT2A and 5-HT2B receptor blockade either as at least two separate compounds each capable of blocking one receptor or one compound capable of blocking both receptors for treating or preventing pulmonary arterial hypertension (claims 1 – 2) (PAH) (page 1 paragraph 0002). Moreover, Amer’707 teach that in pulmonary hypertension the blood pressure in the pulmonary artery generally exceeds 25 mmHg at rest (claim 3) and 30 mmHg with exercise (page 1 paragraph 0004). Additionally, Amer’707 teach the administration of 5-HT2A and 5-HT2B receptor antagonists as a generally water soluble non-toxic pharmaceutically acceptable addition salt such as a basic or acidic addition salt such as for the acidic addition salt with such relatively non-toxic organic or inorganic acids as hydrochloric (claim 8) (page 2 paragraph 0031). Furthermore, Amer’707 teach that pharmaceutical compositions comprising 5-HT2A and 5-HT2B receptor antagonists may be taken orally (claim 10); parenterally (claim 11), by intravenous, subcutaneous, or intramuscular injection; or by inhalation therapy; or transdermally (claim 9) (page 2 paragraph 0033).
Moreover, Amer’707 teach a suitable dose range of from 0.05 – 100 mg per kg of body weight (claim 7) (page 2 paragraph 0036). While Amer’707 is silent about the average weight in mg one of ordinary skill in the art would be able to convert the dosage range taught above by the average kg of a human that is about 60 kg to get a dosage range of 3 – 6000 mg. Thus in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (MPEP 2144.05(I)).
However, Amer’707 fails to teach whether the 5-HT2A and 5-HT2B receptor antagonists is desipramine (claims 1 and 8).
Nevertheless, Todd et. al. teach a decrease in the binding to the 5-HT2A receptor in Male Sprague-Dawley rats weighing 250 – 300 g or 0.250 - .300 kg treated with 10 mg/kg/day of desipramine HCl (DMI) (claims 1, 8, 15 and 18) (page 366 paragraph 1). Thus Todd et. al. suggest that in the Male Sprague-Dawley rat model DMI acts behaves as a 5-HT2A receptor antagonists.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Amer’707 for a method of treating pulmonary arterial hypertension in view of Todd et. al., that is to us DMI as one of the 5-HT2A receptor antagonists. One of ordinary skill in the art would have been motivated to make this modification and have a reasonable expectation of success because continues treatment with DMI decreased the binding to the 5-HT2A receptor in Male Sprague-Dawley rats.
Claims 12 – 20 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication US 2010/0099707 A1 to Amer (herein after Amer’707; cited on IDS dated May 21st, 2024) and Todd et. al. ((1995), Chronic Administration of the Antidepressants Phenelzine, Despiramine, Clomipramine, or Maprotiline Decreases Binding to 5-Hydroxytryptaminea2A Receptors Without Affecting Benzodiazepine Binding Sites in Rat Brain, Cellular and Molecular Neurobiology, 15, 361 – 370; cited on IDS dated May 21st, 2024) as applied to claims 1 – 3, and 7 – 11 above, and further in view of US Patent No. US 7893050 B2 to Fong (herein after Fong’050; cited on IDS dated May 21st, 2024).
The teachings of Amer’707 and Todd et. al. as they relate to claim 1, from which claims 12 – 20 depend, are given previously in this office action and are fully incorporated here.
However, the prior art of Amer’707 and Todd et. al. fail to teach a method comprising an additional agent effective to treat pulmonary hypertension (claims 12, 15, and 18) wherein the additional is phosphodiesterase inhibitors, calcium channel blockers, endothelin receptor antagonists, inotropic agents, prostacyclin pathway agonists, anti-coagulants, guanylate cyclase stimulators, PDE-5 inhibitors, or a combination thereof (claims 13, 16 and 19). Additionally, the prior art of Amer’707 and Todd et. al. fail to teach a wherein at least one additional agent comprises one or more of avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, zaprinast, icariin, amlodipine, nifefipine, diltiazem, bosentan, ambrisentan, sitaxsentan, macitentan, riociguat, toprimate, fusadil, warf arin, digoxin, epoprostenol, treprostinil sodium, iloprost, selexipag, or a combination thereof (claims 14, 17, and 20).
Nevertheless, Fong’050 teach Rho-kinase inhibitors (claims 12, 15, and 18), such as fasudil (claims 14, 17, and 20), in combination with a prostacyclin or prostacyclin agonist (claims 13, 16 and 19), such as iloprost (claims 14, 17, and 20) for treating and/or preventing pulmonary arterial hypertension ("PAH") (column 1 lines 14 – 18). Furthermore, Fong’050 teach other preferred embodiments wherein the Rho-kinase inhibitor may be used in therapeutic combinations with other agents, such as for example, endothelin receptor antagonists, PDE inhibitors, calcium channel blockers, 5-HT2A antagonists (such as sarpogrelate), selective serotonin reuptake inhibitors (such as fluoxetine), statins, and vascular remodeling modulators (such as Gleevec) for the treatment and/or prevention of PAH and/or stable angina (column 1 lines 19 – 26).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Amer’707 and Todd et. al. for a method for treating pulmonary arterial hypertension comprising administering desipramine hydrochloride as the 5-HT2A receptor in further view of Fong’050, that is, in combination with fasudil and sildenafil. One would have been motivated to make this combination and have a reasonable expectation of success because 5-HT2A receptor antagonists, fasudil, and sildenafil taught in the prior art to treat pulmonary arterial hypertension. As stated in In re Kerkhoven, 626 F.2d 846, 205 USPQ 1069, at page 1072 (CCPA 1980): It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (CCPA 1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.
Claims 4 – 6 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication US 2010/0099707 A1 to Amer (herein after Amer’707; cited on IDS dated May 21st, 2024) and Todd et. al. ((1995), Chronic Administration of the Antidepressants Phenelzine, Despiramine, Clomipramine, or Maprotiline Decreases Binding to 5-Hydroxytryptaminea2A Receptors Without Affecting Benzodiazepine Binding Sites in Rat Brain, Cellular and Molecular Neurobiology, 15, 361 – 370; cited on IDS dated May 21st, 2024) as applied to claims 1 – 3, and 7 – 11 above, and further in view of Chemla et. al. ((2004), New Formula for Predicting Mean Pulmonary Artery Pressure Using Systolic Pulmonary Artery Pressure*, Chest, 126, 1313-1317).
The teachings of Amer’707 and Todd et. al. as they relate to claim 1, from which claims 4 – 6 depend, are given previously in this office action and are fully incorporated here.
However, the prior art of Amer’707 and Todd et. al. fail to teach a method wherein the patient has a resting pulmonary arterial pressure greater than 40 mm Hg (claim 4); wherein desipramine or salt thereof is administered in an amount effective to lower resting pulmonary arterial blood pressure to a level no greater than 18 mmHg (claim 5); and wherein desipramine or salt thereof is administered in an amount effective to lower resting pulmonary arterial blood pressure at least 5% relative to the resting pulmonary arterial blood pressure prior to commencing treatment (claim 6).
Nevertheless, Chemla et. al. teach that pulmonary hypertension (PH) is characterized by the chronic elevation of pulmonary artery pressure (page 1313 column 1 paragraph 1). Additionally, Chemla et. al. teach that in most studies, PH is diagnosed on the basis of an increased mean pulmonary artery pressure (MPAP) at rest, and various threshold values have been proposed, namely, 18 (claim 5), 20, or 25 mm Hg (page 1313 column 1 paragraph 1 and column 2 paragraph 1). Furthermore, Chemla et. al. teach that in other studies Doppler-derived SPAP values of > 40 to 50 mmHg (claim 4) have been used to define PH (page 1314 column 1 paragraph 1). Thus Chemla et. al. teach that because MPAP and SPAP are used interchangeably to define PH, it is currently accepted that MPAP and SPAP provide a redundant estimate of the state of pulmonary circulation (page 1314 column 1 paragraph 1).
While claim 5 recites wherein desipramine or salt thereof is administered in an amount effective to lower resting pulmonary arterial blood pressure to a level no greater than 18 mmHg, the prior art of Chemla et. al. teach that 18 mmHg resting pulmonary arterial blood pressure is the lower cut off point for diagnosing a patient with PH. Thus it would have been obvious to one of ordinary skill to in the art to administer desipramine or salt in an effective amount to lower resting pulmonary arterial blood pressure to a level no greater than 18 mmHg to effectively treat a patient with PAH so that the patient no longer has PAH.
While the prior art of Chemla et. al. is silent about a method wherein desipramine or salt thereof is administered in an amount effective to lower resting pulmonary arterial blood pressure at least 5% relative to the resting pulmonary arterial blood pressure prior to commencing treatment (claim 6) the result of a 5% lowering of the resting pulmonary arterial blood pressure would naturally flow from to lower resting pulmonary arterial blood pressure to a level no greater than 18 mmHg.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Amer’707 and Todd et. al. for a method for treating pulmonary arterial hypertension comprising administering desipramine hydrochloride as the 5-HT2A receptor in further view of Chemla et. al., that is, wherein the patient has a resting pulmonary arterial pressure greater than 40 mm Hg and upon administering the resting pulmonary arterial blood pressure is lower to a level no greater than 18 mmHg or lower resting pulmonary arterial blood pressure at least 5% relative to the resting pulmonary arterial blood pressure. One of ordinary skill in the art would be motivated to make this modification and have a reasonable expectation of success 18 mmHg resting pulmonary arterial blood pressure is the lower cut off point for diagnosing a patient with PH.
Conclusion
Claims 1 – 20 are rejected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682