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 .
Election/Restrictions
2. Applicant’s election without traverse of the species of (i) the first non-oral therapeutic agent: parenteral treprostinil, (ii) the second oral therapeutic agent: oral treprostinil, (iii) the additional agent: phosphodiesterase-5 inhibitor, in the reply filed on March 18, 2026 is acknowledged with appreciation.
3. Claims 1-21 are readable on the elected species.
4. The non-elected species are currently withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim, i.e., claims 22 and 23 are presently withdrawn as directed to non-elected subject matter.
5. Claims 1-21 are under examination with the elected species and are the subject of this office action.
Information Disclosure Statement
6. The information disclosure statements (IDS) submitted on November 20, 2023, and April 2, 2024, are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner, please refer to the signed copies of Applicant’s PTO-1449 form, attached herewith.
Claim Objections
7. Claim 9 is objected to for reciting the limitation “orally administered” twice, which is redundant, i.e., the claim recites:
“wherein the orally administered therapeutic agent is an orally administered form of treprostinil, a salt, an ester, or a prodrug thereof,” [emphasis added].
Claim Rejections - 35 USC § 112(b)
8. 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.
9. Claims 1-21 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.
10. Claim 1 recites the limitation of: “wherein the first therapeutically effective amount of non-oral therapeutic agent is sufficient to allow for an increased amount of the orally administered therapeutic agent to thereafter be administered compared to a subject who was not previously treated with the non-oral therapeutic agent,” in lines 5-7 which is not only clunky but indefinite because it is unclear how the increased amount compares to the reference amount. The claim is also unclear regarding the recitation of “compared to a subject…” which is confusing because it is not clear how said amount of orally administered therapeutic agent is compared with a subject.
In view of a broadest reasonable interpretation of the claim, the above recitation is construed as follows:
“wherein the therapeutically effective amount of the non-oral therapeutic agent allows for an increased amount of the orally administered therapeutic agent to be administered, as compared to the amount of oral therapeutic agent administered to a subject who has not been previously treated with the non-oral therapeutic agent.”
11 Claims 2-21 are rejected as being dependent upon and including all of the limitations of claim 1.
12. Claim 9 is rejected as being indefinite because it is not clear what is embraced by the term “form,” because the claim recites “…form of treprostinil, a salt, an ester, or a prodrug thereof” in line 2, yet in the Specification, Applicant states that: “[i]n some embodiments, the form of treprostinil used may be a pharmaceutically acceptable salt or ester, or a prodrug of treprostinil,” (paragraph [0026]). That is, the claim presently recites the form of a form of treprostinil, which is confusing.
Clarification is requested.
Claim Rejections - 35 USC § 112(a)
12. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
13. Claims 1-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
14. In particular, support cannot be found for the full scope of non-oral therapeutic agents and oral therapeutic agents embraced by claim 1, as well as the additional therapeutic agents embraced by claim 18.
15. The MPEP §2163 states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. In the case of chemical entities, Applicant's attention is further directed to Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), which notes that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, “not a mere wish or plan for obtaining the claimed chemical invention.” While the court recognizes that, “[i]n claims involving chemical materials, generic formulae usually indicate with specificity what the generic claims encompass” (Id.), it is also recognized that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim and/or the genus must be sufficiently detailed to show that applicant was in possession of the claimed invention as a whole (see Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991)). If a genus has substantial variance, the disclosure must present a sufficient number of representative species that encompass the genus in order to adequately describe the genus (i.e., the disclosure must describe a sufficient variety of species to reflect the variation within that genus). See MPEP § 2163. Otherwise, as stated by the court in Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company (Fed. Cir. 2010), “a generic claim may define the boundaries of a vast genus of chemical compounds, and yet the question may still remain whether the specification, including original claim language, demonstrates that the Applicant has invented species sufficient to support a claim to a genus. The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result, i.e., “therapeutic agent.” But the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.”
16. It is evident that the genus of drugs embraced by the claims has substantial variance, i.e., the scope of “non-oral therapeutic agent” and “orally administered therapeutic agent” (claim 1) and “additional therapeutic agents” (claim 18) presently recited encompass any/all known or yet unknown biologically active compound, drug, substance, or molecule that is capable of treating or alleviating at least one disease, disorder or medical condition, without limit, which includes hundreds of millions of possible agents, and potentially billions of agents, thus it is evident that the claims are extremely broad.
17. Further, the generic recitation of “therapeutic agent” defines an agent both by its intended use and its effect, reaching through and embracing any future/ yet unknown agents capable of treating or alleviating at least one disease, disorder or medical condition. The recited genus of “therapeutic agents” embraces hundreds of millions of biologically active compounds, drugs, substances, or molecules that are capable of treating or alleviating at least one disease, disorder or medical condition, without limit, and which bear no structural resemblance to one another what-so-ever. Yet, the instant Specification discloses the activity of only one non-oral therapeutic agent (subcutaneous or intravenous treprostinil) and only one orally administered therapeutic agent (oral treprostinil) as broadly recited by the claims.
18. Regarding the limitation that each agent is “for treating pulmonary hypertension,” while the use of a descriptive clause, i.e. “for the treatment of…,” when referring to the contemplated use (i.e. “intended use”) of a claimed compound is proper, it is not a limitation and thus of no significance in determining the patentability thereof, please refer to In re Thomas (CCPA 1949) 178 F2d 412, 84 USPQ 132. Therefore the limitation “for treating pulmonary hypertension” does not impose any limitation on the recited non-oral and orally administered therapeutic agents.
19. While the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad generic. For example, in In re Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d 1008 (Fed. Cir. 1989). In the instant case, it is similarly determined that the disclosure of just one non-oral therapeutic agent (parenteral treprostinil) and only one orally administered therapeutic agent (oral treprostinil) does not adequately describe a genus embracing hundreds of millions of possible agents. That is, the Specification does not disclose a sufficient variety of species to reflect the breadth of the possible compound selections recited in the claims.
20. The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate”). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of non-oral therapeutic agent and orally administered therapeutic agent as recited in the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
21. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
22. Claims 1-21 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of pulmonary hypertension in a subject in need thereof comprising administering a first therapeutically effective amount of parenteral Treprostinil (subcutaneous or intravenous) and followed by orally administered treprostinil to said subject, is not considered enabled for treating any/all types of pulmonary hypertension in a subject in need thereof, comprising administering a therapeutically effective amount of any/ all non-oral therapeutic agent(s) followed by the administration of any/all oral therapeutic agent(s) to said patient (and any additional therapeutic agents). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
23. The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
24. Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the instant case, the claimed invention is drawn to:
a method of treating pulmonary hypertension comprising administering to a subject suffering from pulmonary hypertension a first therapeutically effective amount of a non-oral therapeutic agent for treating pulmonary hypertension followed by an orally administered therapeutic agent for treating pulmonary hypertension, wherein the first therapeutically effective amount of non-oral therapeutic agent is sufficient to allow for an increased amount of the orally administered therapeutic agent to thereafter be administered compared to a subject who was not previously treated with the non-oral therapeutic agent.
25. The Relative Skill of those in the Art: Those practitioners who treat pulmonary hypertension of any type (medical clinicians, pharmacists and/or pharmaceutical chemists) presumably would be highly skilled in the art.
26. The State of the Prior Art and the Level of Predictability in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
27. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that the scope of “therapeutic agent(s)” as presently recited by the claims encompasses any/all known or yet unknown biologically active compound, drug, substance, or molecule that is capable of treating or alleviating at least one disease, disorder or medical condition, without limit, which includes hundreds of millions of possible agents, and potentially billions of agents, thus it is evident that the claims are broad. Further, the generic recitation of “therapeutic agent” defines an agent both by its intended use and its effect, reaching through and embracing any future/ yet unknown agents capable of treating or alleviating at least one disease, disorder or medical condition.
28. The state of the art regarding treatment of pulmonary hypertension of any type according to Mayo Clinic (webpage printout of Pulmonary hypertension - Diagnosis and treatment - Mayo Clinic) is that pulmonary hypertension is difficult to diagnose, even in more advanced stages, requiring radiographs, EKG, Echocardiogram, right heart catheterization, stress tests, CT scans, MRI, lung function tests, sleep studies, V/Q scans, and/or lung biopsies. Mayo Clinic teaches that pulmonary hypertension is sorted into five groups, depending on cause: Pulmonary arterial hypertension (idiopathic); pulmonary hypertension caused by left-sided heart disease; pulmonary hypertension caused by lung disease; pulmonary hypertension caused by blockage in the pulmonary artery; pulmonary hypertension caused by blood disorders, inflammatory disorders, kidney disease or Eisenmenger syndrome; and can be comorbid/ cause complications including right-sided heart enlargement and heart failure, blood clots, arrhythmias, bleeding in the lungs, and pregnancy complications. Mayo Clinic teaches that pulmonary hypertension is challenging to treat: there is no cure for pulmonary hypertension, and it often takes some time to find the best pulmonary hypertension treatment as it can have different causes. Mayo Clinic goes on to teach that treatments are often complex, and involve vasodilators, sGC stimulators, endothelin receptor antagonists, PDE5 inhibitors, calcium channel blockers, blood thinners, digoxin, diuretics, oxygen therapy, atrial septostomy, lung or heart transplant. Thus it is evident that the claimed method of treatment as a whole is complex and unpredictable.
29. Applicants are claiming a method of treating any/ all types of pulmonary hypertension, by administering any first therapeutically effective amount of a non-oral therapeutic agent for treating pulmonary hypertension followed by any orally administered therapeutic agent for treating pulmonary hypertension (and any additional therapeutic agents recited by claim 18). As such, the claimed method is not only unpredictable but extremely broad, and the Specification fails to enable the skilled artisan to use the instant method to treat pulmonary hypertension comprising administering any non-oral therapeutic agent for treating pulmonary hypertension followed by any orally administered therapeutic agent for treating pulmonary hypertension.
30. Even though the Specification discloses one non-oral therapeutic agent (treprostinil administered subcutaneously or intravenously) and one orally administered therapeutic agent which may have been identified as having therapeutic efficacy against pulmonary hypertension (Example 1), as a practical matter the use of any non-oral and oral therapeutic agents for treatment across the broad range of all types of pulmonary hypertension as claimed, remains extremely unpredictable. It is noted that the pharmaceutical art generally is unpredictable, requiring each embodiment to be individually assessed for physiological activity. The court in In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) held that, “in cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.'' In other words, the more unpredictable an area the more specific enablement is needed in order to satisfy the statute.
31. Hence, in the absence of a showing of correlation between the full scope of possible therapeutic agents currently encompassed by the claims, as capable of treating any/all types of pulmonary hypertension, one of skill in the art is unable to fully predict possible results from the recited method. There is simply not enough evidence to be found in the literature suggesting that Applicant’s compounds are capable of being used in the manner recited, to treat any/all types of pulmonary hypertension as encompassed by the claims. In essence, there is no absolute predictability in pharmacology, even with compounds whose properties have been determined, despite the extraordinarily high skill possessed by the ordinary artisan.
32. The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is determined by the Specification and the working examples.
33. In the instant case, the Specification demonstrates the treatment of pulmonary arterial hypertension in a patient in need thereof, comprising administering just one non-oral therapeutic agent, parenteral tresprostinil (intravenous or subcutaneous) at an initial dose of 2 ng/kg/min which is titrated for 2-8 weeks up to 20 ng/kg/min, followed by the administration of just one oral therapeutic agent, oral tresprostinil, (see Example 1). The Specification fails to demonstrate the administration of any other non-oral therapeutic agent and any other oral therapeutic agent for the treatment of pulmonary hypertension whatsoever, in vitro or in vivo.
34. The Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation.” Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright, 999 F.2d 1557 (Fed. Cir. 1993) (emphasis added).
35. At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
36. Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims." Amgen, Inc, v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
37. As to the first inquiry, as discussed above, the claims are drawn to a method of treating pulmonary hypertension comprising administering to a subject suffering from pulmonary hypertension a first therapeutically effective amount of any non-oral therapeutic agent for treating pulmonary hypertension followed by any orally administered therapeutic agent for treating pulmonary hypertension, wherein the first therapeutically effective amount of non-oral therapeutic agent is sufficient to allow for an increased amount of the orally administered therapeutic agent to thereafter be administered compared to a subject who was not previously treated with the non-oral therapeutic agent.
Considering that the claimed “non-oral therapeutic agent” and “orally administered therapeutic agent” of claim 1 and “additional therapeutic agents” of claim 19 as presently recited encompass any/all known or yet unknown biologically active compound, drug, substance, or molecule that is capable of treating or alleviating at least one disease, disorder or medical condition, without limit, which includes hundreds of millions of possible agents, if not billions of agents, it is evident that the claims are extremely broad.
38. Further, the generic recitation of “therapeutic agent” defines an agent both by its intended use and its effect, reaching through and embracing any future/ yet unknown agents capable of treating or alleviating at least one disease, disorder or medical condition. The recited genus of “therapeutic agents” embraces hundreds of millions of biologically active compounds, drugs, substances, or molecules that are capable of treating or alleviating at least one disease, disorder or medical condition, without limit, and which bear no structural resemblance to one another what-so-ever. Yet, the instant Specification discloses the activity of only one non-oral therapeutic agent (subcutaneous or intravenous treprostinil) and only one orally administered therapeutic agent (oral treprostinil) as broadly recited by the claims.
39. Regarding the limitation that each agent is “for treating pulmonary hypertension,” while the use of a descriptive clause, i.e. “for the treatment of…,” when referring to the contemplated use (i.e. “intended use”) of a claimed compound is proper, it is not a limitation and thus of no significance in determining the patentability thereof, please refer to In re Thomas (CCPA 1949) 178 F2d 412, 84 USPQ 132. Therefore the limitation “for treating pulmonary hypertension” does not impose any limitation on the recited non-oral and orally administered therapeutic agents.
As such, the claim is extremely broad with respect to the disclosure. The second inquiry is discussed in detail below.
40. Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to any/all types of pulmonary hypertension in a subject in need thereof, comprising administering a therapeutically effective amount of any/ all non-oral therapeutic agent(s) followed by the administration of any/all oral therapeutic agent(s) to said patient. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of the recited use of non-oral and oral “therapeutic agent(s)” for the treatment of all types of pulmonary hypertension, with respect to the disclosure, since “therapeutic agent,” without limit, encompasses hundreds of millions of agents, if not billions, whereas the instant Specification discloses the administration of only one such non-oral and one such oral therapeutic agent exerting the disclosed activity for treating pulmonary arterial hypertension.
41. After applying the Wands factors and analysis to the instant claims, in view of the Applicant’s entire disclosure and the state of the art, it is concluded that the practice of the invention as claimed would not be enabled by the written disclosure.
It is suggested to limit the scope of pulmonary hypertension to be treated to that which is enabled by Applicants' disclosure (pulmonary arterial hypertension), as well as limiting the scope of non-oral and oral therapeutic agents such that they bear a reasonable correlation with the disclosure, i.e., limit the non-oral therapeutic agent to subcutaneous or intravenous treprostinil and limit the oral therapeutic agent to treprostinil.
Claim Rejections - 35 USC § 103
42. 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.
43. 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.
44. 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.
45. Claims 1-5, 9-14 and 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over Chakinala et al., (The Journal of Heart and Lung Transplantation 2017, cited on Applicant’s IDS of April 2, 2024), in view of Kumar et al., (Clin Pharmacokinet 2016, cited on Applicant’s IDS of April 2, 2024).
Claim 1 is drawn to a method for treating pulmonary arterial hypertension (claim 17) comprising administering to a subject suffering from pulmonary hypertension:
(a) a first therapeutically effective amount of a non-oral therapeutic agent for treating pulmonary hypertension (more specifically, parenteral treprostinil that is administered intravenously or subcutaneously (claims 2-5)), followed by
(b) an orally administered therapeutic agent for treating pulmonary hypertension (more specifically, oral treprostinil (claims 9 and 21)),
wherein the first therapeutically effective amount of non-oral therapeutic agent is sufficient to allow for an increased amount of the orally administered therapeutic agent to thereafter be administered compared to a subject who was not previously treated with the non-oral therapeutic agent.
*In view of a broadest reasonable interpretation, the last 4 lines of claim 1 are construed to mean:
“wherein the therapeutically effective amount of the non-oral therapeutic agent allows for an increased amount of the orally administered therapeutic agent to be administered, as compared to the amount of oral therapeutic agent administered to a subject who has not been previously treated with the non-oral therapeutic agent.”
46. Chakinala et al. teach the advantages of treating pulmonary arterial hypertension (PAH) in a subject in need thereof by transitioning from parenteral treprotstinil to oral treprostinil, which has significantly less delivery-related safety and convenience limitations (see abstract). Chakinala et al. teach that the administration of a therapeutically effective amount of parenteral treprostinil (subcutaneous or intravenous), followed by a transition of less than 4 weeks to oral treprostinil resulted in successful treatment of PAH (see Table 1 at page 195), however Chakinala et al. are silent to the limitation that an increased amount of oral tresprostinil is administered in comparison to the amount of oral treprostinil administered to a subject who has not been previously treated with non-oral treprostinil.
47. However, Kumar et al. teach the administration of oral treprostinil as a replacement for parenteral therapy, wherein the oral treprostinil dose equivalence is calculated as follows:
total daily dose of oral treprostinil (mg) = 0.0072 x Remodulin® dose (ng/kg/min) x weight (kg)
(see page 1502, right column, under “2.3.6 Oral Treprostinil as a Replacement for Parenteral Therapy”). Thus the total daily dose of oral treprostinil is 0.0072 X a parenteral dose of from 25 to 111 ng/kg/min X average human weight of 77 kg = 13.86 mg to 61.54 mg. The range of 13.86 mg to 61.54 mg oral Treprostinil calculated in the above formula is greater than the amount of oral Treprostinil suggested by Kumar et al. as a starting dose, i.e., 0.25 mg twice daily or 0.125 mg three times daily wherein mean doses in a controlled clinical trial were 3.4 mg twice daily, and an open label extension study reported mean doses of 3.1, 3.6, and 4.1 mg twice daily at 6, 12 and 24 months (page 1500, left column, last two paragraphs).
48. Thus, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to treat PAH in a subject in need thereof by administering parenteral tresprostinil followed by replacement therapy of oral treprostinil, wherein an increased dose of oral tresprostinil is administered relative to the dose of oral treprostinil recommended for a subject who has not been previously treated with parenteral treprostinil.
As such, claims 1-5, 9, 17 and 21 are prima facie obvious.
Claim 6 is drawn to claim 3, wherein the parenteral treprostinil is initiated at a dose of 2 ng/kg/min, wherein the parenteral treprostinil is titrated to a minimum dose of 20 ng/kg/min over at least two weeks (claim 7), and wherein the parenteral treprostinil is titrated to a minimum dose of 20 ng/kg/min over a period from about two weeks to about eight weeks (claim 8).
49. Chakinala et al. do not teach wherein the dose of parenteral treprostinil is initiated at a dose of 2 ng/kg/min that is titrated up to a minimum dose of 20 ng/kg/min, over a period of about two weeks to about eight weeks.
50. Yet, Kumar et al. teach that parenteral treprostinil (subcutaneous or intravenous) is administered for the treatment of PAH in a subject in need thereof, wherein the infusion rate is initiated at 1.25 ng/kg/min. Regarding Applicant’s recited initial dose of parenteral treprsotinil of 2 ng/kg/min, dose regimen optimization is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art. Moreover, the determination of known effective amounts of known active agents to be administered to treat the same disease is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. As Kumar et al. teach an incremental dosage regimen for parenteral treprostinil that is used to treat PAH, and how to adjust that dosage based on clinical response, the dosage variation based on tolerability is considered a result effective variable.
51. Kumar et al. teach that the initial dose is increased in increments of 1.25 ng/kg/min per week for the first four weeks and increased to increments of 2.5 ng/kg/min per week, wherein dosage adjustments can occur more frequently if tolerated (see page 1497, left column, under “2.1 Remodulin (Parenteral Treprostinil Sodium) Dosing Overview”). Thus, an initial dose of 2 ng/kg/min increased by 2 ng/kg/min per week for a period of four weeks, followed by an increase of at least 2.5 ng/kg/min per week for a period of five weeks, results in a dose of 20 ng/kg/min over a period of nine weeks. A period of “about eight weeks” required by claim 8 is reasonably suggested by a period of nine weeks because the use of the modifier “about” indicates that a precise amount is not required.
52. Thus in view of the teaching of Kumar et al., one of skill in the art before the effective filing date of the claimed invention would have been motivated to titrate the initial dose of parenteral treprostinil from 2 ng/kg/min up to 20 ng/kg/min over a period from about two weeks to about eight weeks, with a reasonable expectation of success.
As such, claims 6-8 are prima facie obvious.
Claim 10 is drawn to claim 9, and limits wherein the orally administered form of treprostinil is administered two times per day, or is administered three times per day (claim 11).
53. Chakinala et al. teach that oral treprostinil was initially administered twice daily but the higher dose of oral treprostinil was better tolerated when administered three times daily (page 195, left column, third paragraph), which meets the limitations of instant claims 10 and 11. Thus one skilled in the art before the effective filing date of the claimed invention would have been motivated to administer oral treprostinil two times per day or three times per day, as guided by the prior art, with a reasonable expectation of success.
As such, claims 10 and 11 are prima facie obvious.
Claim 12 is drawn to claim 9, wherein the orally administered form of treprostinil is titrated up to at least 12 mg per day from an initial orally administered dose of 1 mg per day over a period of up to 21 days.
Claim 13 is drawn to claim 9, wherein the orally administered form of treprostinil is titrated up to at least 12 mg per day from an initial orally administered dose of 0.5 mg per day over a period of up to 21 days.
54. Chakinala et al. additionally teach a dose escalation of oral treprostinil starting from an initial dose of 5.5 ±3.4 mg per day titrated up to 34.2±11.1 mg per day over a period of one week, which meets the limitation of being titrated to “at least 12 mg per day… over a period of up to 21 days” required by instant claims 12 and 13.
55. Regarding the initial orally administered dose of 1 mg/day required by claim 12, the initial dose of 5.5 ±3.4 mg per day disclosed by Chakinala et al. embraces a dose of 2.1 mg/day. Thus it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to reduce the initial orally administered dose of treprostinil from 2.1 mg to 1 mg (required by claim 12) or to 0.5 mg (required by claim 13), because optimization of parameters is a routine practice that would be obvious for one of skill in the art to employ. And, dose regimen optimization is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art, with a reasonable expectation of success.
As such, claims 12 and 13 are prima facie obvious.
Claim 16 is drawn to claim 1, wherein the subject’s six-minute walk distance increases.
56. Chakinala et al. additionally teach that from baseline to the week 24 assessment following transition to oral treprostinil, the 6-minute walk distance increased from 460 ± 98 m to 472 ± 96 m, which meets the limitation of claim 16.
57. Thus, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention that following a transition to oral treprostinil from parenteral treprostinil in a subject in need thereof, the six minute walk distance of said subject would increase, with a reasonable expectation of success.
As such, claims 14 and 16 are prima facie obvious.
58. Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Chakinala et al., (The Journal of Heart and Lung Transplantation 2017), in view of Kumar et al., (Clin Pharmacokinet 2016) as applied to claims 1-5, 9-14 and 16-23, above, further in view of Coons et al., (Pulm Circ 2016).
Claim 1 is addressed in detail, above.
Claim 14 is drawn to claim 1, wherein at least one side effect selected from the group consisting of headache, nausea, and vomiting improves after transition to the orally administered therapeutic agent.
59. Chakinala et al. in view of Kumar et al. suggest the treatment of PAH in a subject in need thereof by administering parenteral tresprostinil followed by replacement therapy of oral treprostinil, wherein an increased dose of oral tresprostinil is administered to said subject relative to the dose of oral treprostinil recommended for a subject who has not been previously treated with parenteral treprostinil, but do not teach the improvement in a side effect selected from side effect selected from the group consisting of headache, nausea, and vomiting, after transition to the orally administered therapeutic agent.
60. Yet, Kumar et al. teach that common risks/adverse effects resulting from parenteral treprostinil administration include headache and nausea (see Table 1 at page 1496).
61. And, Coons et al. disclose a case series of patients that transitioned from parenteral or inhaled treprostinil to oral treprostinil, in particular Patient 8, who transitioned from parenteral (subcutaneous) treprostinil to oral treprostinil with no adverse events (see Table 2 at page 134).
62. Thus, in view of the combined prior art of record, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention that following the transition of parenteral treprostinil to oral treprostinil, the side effects of headache and nausea associated with administration of parenteral treprostinil would improve, with a reasonable expectation of success.
As such, claim 14 is prima facie obvious.
63. Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Chakinala et al., (The Journal of Heart and Lung Transplantation 2017), in view of Kumar et al., (Clin Pharmacokinet 2016) as applied to claims 1-5, 9-14 and 16-23, above, further in view of Tonelli et al., (J Am Soc Echocardiogr 2014).
Claim 1 is addressed in detail, above.
Claim 15 is drawn to claim 1, wherein the area of the subject’s right atrium decreases.
64. Chakinala et al. in view of Kumar et al. suggest the treatment of PAH in a subject in need thereof by administering parenteral tresprostinil followed by replacement therapy of oral Treprostinil, wherein an increased dose of oral tresprostinil is administered to said subject relative to the dose of oral treprostinil recommended for a subject who has not been previously treated with parenteral treprostinil, but do not teach a resulting decrease in the right atrium.
65. Yet, Tonelli et al. disclose echocardiographic changes in patients with pulmonary arterial hypertension receiving parenteral prostacyclin therapy, including parenteral treprostinil (intravenous and subcutaneous), in particular the right atrial area:
“When compared to the baseline, the follow-up echocardiogram showed a reduction in the right atrial area,” (see Abstract: Results and page 18, Table 2).
66. Thus, one of skill in the art would reasonably expect the result of a decrease in the area of the right atrium of a subject that has received parenteral prostacyclin therapy, including parenteral Treprostinil. It would have been obvious to one skilled in the art before the effective filing date of the claimed invention that when treating PAH in a subject in need thereof by administering parenteral tresprostinil followed by replacement therapy of oral Treprostinil, wherein an increased dose of oral tresprostinil is administered to said subject relative to the dose of oral treprostinil recommended for a subject who has not been previously treated with parenteral treprostinil, a decrease in the right atrium area would occur following treatment with said parenteral Treprostinil.
As such, claim 15 is prima facie obvious.
67. Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Chakinala et al., (The Journal of Heart and Lung Transplantation 2017), in view of Kumar et al., (Clin Pharmacokinet 2016) as applied to claims 1-5, 9-14 and 16-23, above, further in view of Mandras et al., (Journal of Cardiovascular Pharmacology and Therapeutics 2021, cited on Applicant’s IDS of November 30, 2023).
Claim 1 is addressed in detail, above.
Claim 18 is drawn to claim 1, wherein the method comprises treating the subject with additional therapeutic agents that treat pulmonary hypertension (claim 19), more specifically a phosphodiesterase-5 inhibitor (claim 20).
68. Chakinala et al. in view of Kumar et al. suggest the treatment of PAH in a subject in need thereof by administering parenteral tresprostinil followed by replacement therapy of oral treprostinil, wherein an increased dose of oral tresprostinil is administered to said subject relative to the dose of oral treprostinil recommended for a subject who has not been previously treated with parenteral treprostinil, but do not teach treating the subject with an additional therapeutic agent.
69. Yet, Mandras et al. suggest the benefits of combination therapy for treating PAH, “allowing for simultaneous targeting of more than one of these signaling pathways implicated in disease progression” (see abstract). In particular, Mandras et al. disclose the studies “FREEDOM-C,” “FREEDOM-C2,” and “FREEDOM-EV,” which each evaluate the combination therapy of oral Treprostinil and a PDE5 inhibitor for the treatment of PAH in a subject in need thereof.
70. Thus, one of skill in the art before the effective filing date of the claimed invention would have been motivated to treat PAH in a subject in need thereof by administering parenteral tresprostinil followed by replacement therapy of oral treprostinil, wherein an increased dose of oral tresprostinil is administered to said subject relative to the dose of oral treprostinil recommended for a subject who has not been previously treated with parenteral treprostinil, and administering an additional therapeutic agent that is a PDE5 inhibitor, with a reasonable expectation of success.
As such, claims 18-20 are prima facie obvious.
Conclusion
71. Claims 1-23 are pending in the application. Claims 22 and 23 are presently withdrawn as directed to nonelected subject matter. Claims 1-21 are rejected. No claim is presently allowed.
72. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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