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
Filing Receipt and Priority Date
The filing receipt mailed 05/14/2025 states that the instant application is a CON of application 16/968,530, filed 08/07/2020, which is a 371 of PCT/US2019/017290, filed 02/08/2019, which claims benefit of provisional application 62/628,068, filed 02/08/2018.
The instant application finds support in the provisional application. Therefore the effective filing date is 02/08/2018.
Information Disclosure Sheet
The information disclosure in the parent application (16/968,530) has been considered. No additional IDS has been provided.
Restriction/Species Election
The following elections without traverse are acknowledged.
Applicant has elected Group I, claims 1-22 and 47.
Applicant has further elected the following species: (1) Treprostinil (prostanoid), (2) leucine (excipient). The examiner acknowledges the additional election of (3) pulmonary hypertension.
Applicant states that the elections read on claims 1-5, 7-13, and 47. Claim 7 is drawn to a phospholipid excipient. Therefore, claim 7 is withdrawn as being drawn to a non-elected species.
Claims 6-7, 14-46, and 48 have been withdrawn as being drawn to non-elected invention and species.
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.
Claim 2 is 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 2 states “wherein the plurality of particles has a geometric standard deviation of about 1 to about 3.”
The instant specification does not specify whether this includes a unit of measurement. The claim as well does not specify a unit of measurement. One of ordinary skill in the art would not know the metes and bounds of the claims from the claims or specification.
Claim 5 is 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 5 states “pharmaceutically-acceptable excipient”. Claim 1 states “pharmaceutically acceptable salt”. Claim 5 lacks antecedent basis.
Rejections
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.
The MPEP in section 2143, subsection I gives examples of Rationales for supporting a conclusion of obvious. These rationales are non-exhaustive and include (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Claim(s) 1-5, 8-13 and 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pascoe (US2011/0190313) in view of Zisman (WO2014/110200), Seville (Powder Technology 178 (2007) 40-50), Sandifer (J Appl Physiol, 99: 2363-2368, 2005), and Medarametla (Pulm Circ, 2014;4(1):82-102).
Instant claim 1 is drawn to a pharmaceutical formulation comprising a prostanoid (a) and a compound of formula shown below.
Compound 1
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Claim 1 additionally species that the pharmaceutical formulation is a spray dried powder formulation comprising a plurality of particles with a mass median aerodynamic diameter of about 1 micron to about 5 microns.
Dependent claims 2-3 further specify physical characteristics of the formulation. Claim 2 further includes “wherein the plurality of particles has a geometric standard deviation of about 1 to about 3.” Claim 3 states “wherein the spray dried powder formulation has a fine particle fraction of about 70% to about 99%.”
Dependent claims 8-12 specify amounts of prostanoid (claims 8-10, 12) or the compound 1 above (claim 11).
Dependent claims 4-5 further comprise an excipient which applicant has elected to be leucine.
Dependent claim 13 specifies that the prostanoid is Treprostinil (elected prostanoid).
Independent claim 47 is drawn to a pharmaceutical formulation comprising the compound 1 above, Treprostinil, and leucine and wherein the formulation is a spray dried formulation comprising a plurality of particles wherein the mass median aerodynamic value, the geometric standard deviation, and fine particle fraction are 2.21 μm, 1.79, and 83.6% respectively.
Regarding claims 1, 13 and 47, Pascoe in para. [0075] contemplates the combination of imatinib (referred to as compound I, structure below) and treprostinil.
Pascoe Compound I
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Pascoe in para. [0092] teaches that imatinib is a “tyrosine kinase inhibitor that inhibits PDGFR α and β kinases, AbI, DDR, and c-KIT.
Pascoe teaches the general combination of imatinib and treprostinil, but does not teach instant compound 1, amounts of treprostinil, or leucine as an excipient.
This is addressed by Zisman and Seville.
Zisman in Fig. 18D teaches a compound of structure 2a (PK10571) shown below.
Structure 2a is identical to the compound 1 above.
Zisman Fig. 18D
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Regarding claim 11 and 47, Zisman in para. [0127] teaches administrating doses of compounds of their disclosure. Zisman in para. [0182] teaches administration of PK10571 at 1μM and 10μM. Zisman in para. [0043] states “Fig.18A-D is a graphic representation of PK compounds…showing that all compounds possess a lower IC50 concentration compared to imatinib for inhibiting PDGFBB stimulated AKT phosphorylation in fetal human lung fibroblasts.” Relevant figures are shown below.
Zisman Fig. 18D
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Zisman in para. [0120] contemplates formulations including a dry powder formulation. This is further detailed in paragraphs [0122]-[0124] where inhalable powders with suitable excipients are discussed (para. [0122]). Particle size is discussed in para. [0124] where it states “In formulations intended for administration to the respiratory tract…the active compound is typically configured to have a small particle size, e.g. approximately 5 microns or less, via micronisation techniques and the like.”
Fig. 18A-C
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Zisman in para. [0165] also teaches that imatinib inhibits PDGFBB stimulated AKT phosphorylation where it teaches that the IC50 for imatinib for said inhibition is 1.8 μM. Considering these teachings and the teachings above regarding Fig. 18A-C, one of ordinary skill would know that the imatinib and the PK10571 compound share a target which is PDGFBB. Because of this, one of ordinary skill would find it obvious to swap one compound for the other.
Regarding claims 4-5, Seville teaches amino acid-modified spray dried powders (title). Seville in sec. 3.1 Spray-dried powder characteristics states “A total of 21 spray-dried powder were investigated…The addition of the amino acid dispersibility enhancer caused considerable variation in the yield of powder produced (range 31%-81%)…Only those formulation modified with leucine showed an increase in powder yield at all the amino acid concentrations tested.” Seville additionally states “It has previously been suggested that low spray-drying yields are indicative of cohesive powders that demonstrate poor aerosolization properties, that the addition of formulation excipients may change the physiochemical characteristics of the resultant spray-dried powders, resulting in an improved spray-drying yield. And potentially enhanced aerosolization properties.” Additionally, Seville on p. 42, Table 1 teaches physical properties of leucine as a spray dried powder including particle size.
Pascoe contemplates the combination of kinase inhibitor imatinib with treprostinil. Zisman teaches the instant compound and also teaches that the instant compound has a lower IC50 value than imatinib. Seville teaches leucine as an aerosol excipient for dry powders.
Pascoe, Zisman, and Seville do not explicitly discuss aerosolized treprostinil or the physical characteristics as claim in claims 1-3 (mass median aerodynamic diameter, geometric standard deviation, and fine particle fraction). These are addressed by Sandifer, Medarametla, and Ivey.
Regarding claims 8-10 and 12, Sandifer teaches a comparison between treprostinil administered as an aerosol or intravenously. Sandifer on p. 2364, sec. Experimental protocol teaches administration of 250, 500, and 1000 ng*kg-1*min-1 of treprostinil as an aerosol.
Medarametla in sec. Formulation and aerosol delivery states “PK10453 was dissolved at a concentration of 20 mg/mL in 1 M tosylic acid. Nebulization was performed with a PARI nebulizer with an air pressure of 12,5 PSI. The aerosol droplets were neutralized by ammonia vapor that was passed into the aerosol airstream. The particles were then dried by passage through an annular ring of silica bead cartridges before reaching the exposure chamber…The mass median aerodynamic [of the PK10453 particles] was 2 μm, and the associated geometric standard deviation was 1.6.” PK10453 is identified in Zisman as structure 2 (see Fig. 18D above). The difference between structure 2 and structure 2 is simply the change of a hydroxy group for a methoxy group. The compounds are essentially homologs of each other and one of ordinary skill in the art would expect similar properties for structure 2a (PK10571).
Regarding the “fine particle size” limitation of claim 1 and also regarding claims 2 and 3, Seville on p. 41-42, sec. 2.4 teaches fine particle fraction of its compositions. Seville states “The fine particle fraction (FPF) was calculated as the ratio of FPD to total loaded dose, expressed as a percentage and corrected for actual salbutamol content in each powder.” Seville continues “The mass median aerodynamic diameter (MMAD) of the powder was also derived, defined as the particle size at the 50% mark of a plot of cumulative fraction vs. effective cut-off diameter.”
From these teachings, one can glean that the mass median aerodynamic diameter, geometric standard deviation, and fine particle fraction are physical characteristics that can be manipulated by one of ordinary skill in the art.
Similarly, regarding claims 8-12, which are drawn to dose amounts of treprostinil and a specific concentration of compound 1, the art teaches administration of treprostinil in dosing amounts and also teaches dose amounts of PK10571 (See. Fig. 18B) While these amounts are below the claimed amounts, it is within the skillset of one of ordinary skill to modify the dose amounts or to administer the concentrations taught sufficiently to meet the claimed limitations. For example, one of ordinary skill would be able to administer treprostinil at a rate of 1000 ng*kg-1*min-1 for 5-25 minutes to achieve the claimed dose ranges in claims 8-11. To achieve the doses claimed in claim 12 and 47, one of ordinary skill could simply modify the concentration.
The MPEP section 244.05, subsection II states:
“The adjustment of particular conventional working conditions (e.g., determining result effective amounts of the ingredients beneficially taught by the cited references), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.
“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results.”
The art teaches and/or contemplates at least the combination of imatinib, which inhibits PDGFBB, with treprostinil. The art also teaches PK10571, another PDGFBB inhibitor, has a lower IC50 compared to imatinib, which would give one of ordinary skill in the art motivation to replace imatinib with the PK10571 compound. Dry powder formulations are contemplated by the art. Leucine as a dry powder excipient is also known within the art. The art also teaches that leucine is effective in increasing powder yields compared to other amino acids. The physical limitations which are mass median aerodynamic diameter, geometric standard deviation, and fine particle fraction are physical characteristics that can be easily modified by one of ordinary skill. Similarly, doses and concentrations which are known within the art can also be easily modified.
Therefore, it would have been prima facie obvious to one of ordinary skill within the art to have combined PK10571 with treprostinil and further combine leucine into a dry powder formulation with the claimed physical characteristics and claimed doses and/or amounts at the time of filing with a reasonable assumption of success.
One of ordinary skill would have been motivated to make the modification and combination as PK10571 shows a lower IC50 than imatinib and because leucine has been shown to be effective in increasing powder yield.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US Patent 9,815,815
Claims 1-5, 8-13 and 47 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 57 of U.S. Patent No. 9,815,815 in view of Pascoe (US2011/0190313) in view of Zisman (WO2014/110200), Seville (Powder Technology 178 (2007) 40-50), Sandifer (J Appl Physiol, 99: 2363-2368, 2005), and Medarametla (Pulm Circ, 2014;4(1):82-102).
The reference claims a compound of structure below:
Reference compound
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The compound is identical to the structure 2a of Zisman discussed above. For reasons discussed in the 103 rejection above, the instant claims would be obvious in view of the reference claim.
US Patent 9,925,184
Claims 1-5, 813 and 47 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 77, 81, 82, 86, 87, and 88 of U.S. Patent No. 9,925,184 in view of Pascoe (US2011/0190313) in view of Zisman (WO2014/110200), Seville (Powder Technology 178 (2007) 40-50), Sandifer (J Appl Physiol, 99: 2363-2368, 2005), and Medarametla (Pulm Circ, 2014;4(1):82-102).
The reference claims are drawn to a formulation comprising a compound of formula shown below and at least one excipient.
Reference claim 77
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Reference claim 81 and 82 specify leucine and L-leucine respectively.
The instant claims would be obvious over the reference claims in view of the cited references for reasoning that is similar to the 103 rejection made above.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUISALBERTO GONZALEZ whose telephone number is (571)272-1154. The examiner can normally be reached M-F 8:30-5:30.
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/L.G./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624