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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 15 June 2026 has been entered.
Status of Claims
Receipt is acknowledged of the claim amendments filed on 15 June 2026.
Claims 1-225, 227-228, 231, 233-234, 243-244, 248, 251-253, 257-261 and 263-264 are cancelled.
Claims 226 and 262 have been amended.
Claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256 and 262 are presented for examination herein.
Terminal Disclaimer
The terminal disclaimer filed on 05/22/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on Application Number 18/034,619 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Information Disclosure Statement
The information disclosure statement (IDS) filed 06/25/2026, 08/10/2026 and 09/11/2026 have been considered by the Examiner. A signed and initialed copy of the IDS is included with the instant Office Action.
Rejections Withdrawn
The rejection of claims 260 and 262 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, is withdrawn in view of the claim amendments file 15 June 2026.
The rejection of claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256, 260 and 262 under 35 U.S.C. 103(a) as being unpatentable over MALININ (US 9,255,064; cited in IDS filed 12/04/2023; patent date of 09 February 2016) in view of PAN (CN 1593414 A, date published: 16 March 2005) and THERAPEUTICS INITIATIVE (“Dose Titration: Minimize to Maximize”, October 1995; cited in PTO-892 mailed 03/01/2024; hereafter Therapeutics), is withdrawn in view of the claim amendments file 15 June 2026.
The rejections on the ground of nonstatutory double patenting not reiterated from the previous office action are hereby withdrawn in view of the claim amendments filed 15 June 2026.
New Grounds of Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 262 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 262 recites “a leucine-to-mannitol weight ratio of about 0.40-to-1”, while independent claim 226, which claim 262 is dependent on, recites that the amount of leucine is “from about 29 wt% to about 61 wt%”, so even at the lowest amount of leucine of 29 wt% and lowest amount of the compound of Formula (I) from claim 226, the weight ratio of leucine-to-mannitol of about 0.40-to-1 recited in claim 262 would require an amount of 72.5 wt% of mannitol (e.g., 0.40/1=29/x; [29x1]/.40, x=72.5%) which would add up to more than 100% (e.g., 0.5% (lowest amount of compound) + 29% (lowest amount of leucine) + 72.5%=102%). Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256, 260 and 262 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over MALININ (US 9,255,064; cited in IDS filed 12/04/2023; patent date of 09 February 2016) in view of WEILER (WO 2010/060875 A1, publication date of 03 June 2010), MCINTOSH (US 2014/0294969 A1, publication date of 02 October 2014) and THERAPEUTICS INITIATIVE (“Dose Titration: Minimize to Maximize”, October 1995; cited in PTO-892 mailed 03/01/2024; hereafter Therapeutics) as evidenced by SHARMA (“To scale or not to scale: the principles of dose extrapolation”, British Journal of Pharmacology, 157, 907-921, 2009.
Malinin is primarily directed towards prostacyclin compounds, compositions comprising the same, and methods for treating including pulmonary hypertension (abstract).
Regarding claims 226, 229, 245 and 255-256, Malinin discloses a method for treating pulmonary hypertension (PH) (column 7, lines 10-11) that includes pulmonary administration of a composition comprising the prostacyclin compound that is administered once daily to the patient via including a dry powder inhaler (column 7, lines 24-28). Malinin discloses treprostinil alkyl esters Formula (A):
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl) (column 51, lines 55-58; column 52, Formula (A); column 53, compound C16-TR). Malinin discloses inhaled C16-TR (e.g., R1 is hexadecyl) at a dose of 0.6-18 µg/kg for a rat (e.g., dose for 70 kg person is calculated to be about 6.8 µg to about 203.2 µg (human equivalent dose = dose of rat divided by 6.2) as evidenced by Sharma at Table 1 of Sharma) was well tolerated with no evidence of body weight and organ weight change after dosing for 14 consecutive days (column 82, lines 49-51). Malinin discloses dose of 6-90 µg/kg for dogs (e.g., dose for 70 kg person is calculated to be about 233.3 µg to about 3500 µg (human equivalent dose = dose of dog divided by 1.8) as evidenced by Sharma at Table 1 of Sharma) (column 81, lines 55-62).
Regarding claims 230 and 232, Malinin discloses a method for treating pulmonary hypertension (PH) (column 7, lines 10-11). Malinin discloses that pulmonary hypertension has been classified into five groups by the WHO (e.g., includes class I and class III (e.g., group 1 PH and group 3 PH, respectively)) (column 1, lines 29-48).
Regarding claim 235-236, Malinin discloses that group I is called pulmonary arterial hypertension (PAH) (column 1, lines 30-31).
Regarding claim 237-238, Malinin discloses that group III pulmonary hypertension is characterized as PH associated with lung diseases including interstitial lung diseases (column 1, lines 38-40).
Regarding claim 239, Malinin discloses pulmonary hypertension caused by systemic disorders including sarcoidosis (column 1, lines 44-47).
Regarding claims 240-242, Malinin discloses that the therapeutic response of the patient is including improved exercise capacity (e.g., as measured by the six-minute walk test) compared to pretreatment (column 42, lines 24-32).
Regarding claim 254, Malinin discloses that the pulmonary delivery devices include a capsule-based dry powder inhaler (paragraph bridging columns 48 and 49).
Regarding claim 255, Malinin discloses that each administration (e.g., single dosing session) comprises 1 to 5 doses (puffs (e.g., inhalations)) from a DPI (column 43, lines 9-10).
Malinin does not specifically teach spray-dried dry powder composition consisting of spray-dried particles, wherein the spray-dried particles comprise: (i) from about 0.5 wt% to about 4 wt% of the treprostinil alkyl esters Formula (A) (e.g., Formula (I)), (ii) from about 29 wt% to about 61 wt% leucine, and (iii) the balance being mannitol, wherein the spray-dried powder composition does not contain DSPE-PEG2000. Malinin does not specifically teach titrating an initial dose to the patient’s highest tolerated dose. The deficiencies are made up for by the teachings of Weiler, Mcintosh and Therapeutics.
Weiler is primarily directed towards powders for inhalation that are stable (see abstract and entire English translation of the patent publication).
Regarding claims 226 and 262, Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (e.g., .1% to 50% of the active ingredient; 100/1000=.1, 100/2= 50) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Therefore, Weiler teaches a spray-dried powder consisting of spry-dried particles that comprise active and mannitol that does not require DSPE-PEG2000 because Weiler teaches spray-dried powder that only requires an active and matrix former that includes mannitol (page 3, eighth paragraph and tenth paragraph; page 14, first paragraph; page 16, last paragraph).
Mcintosh is primarily directed towards dry powders for inhalation (abstract).
Regarding claim 226 and 262, Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]).
Therapeutics is primarily directed towards dose titration (see entire literature).
Regarding claims 226 and 245-247, Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page).
Regarding claims 249-250, Malinin discloses inhaled C16-TR (e.g., R1 is hexadecyl) at a dose of 0.6-18 µg/kg for a rat (e.g., dose for 70 kg person is calculated to be about 6.8 µg to about 203.2 µg (human equivalent dose = dose of rat divided by 6.2) as evidenced by Sharma at Table 1 of Sharma) was well tolerated with no evidence of body weight and organ weight change after dosing for 14 consecutive days (column 82, lines 49-51). Malinin discloses dose of 6-90 µg/kg for dogs (e.g., dose for 70 kg person is calculated to be about 233.3 µg to about 3500 µg (human equivalent dose = dose of dog divided by 1.8) as evidenced by Sharma at Table 1 of Sharma) (column 81, lines 55-62).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering once daily a dose of a spray-dried powder consisting of a compound having the following formula:
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl), a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from 0.6-18 µg/kg for a rat (e.g., dose for 70 kg person is calculated to be about 6.8 µg to about 203.2 µg (human equivalent dose = dose of rat divided by 6.2)) and 6-90 µg/kg for dogs (e.g., dose for 70 kg person is calculated to be about 233.3 µg to about 3500 µg (human equivalent dose = dose of dog divided by 1.8) as evidenced by Sharma at Table 1 of Sharma); wherein the spray-dried powder contains matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1; and wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight (e.g., the amount of the active and matrix former (e.g., mannitol) is calculated to range from 0.05%-47.5% and 25%-94.905% (example of calculations: for 5% leucine, 95% of dry powder left and using ratio range of 1:999 to 1:1 taught by Weiler gives .095%-47.5% active (95%x.001(active if 1:999 ratio)=.095%; 95%x.5 (active if 1:1 ratio)) and 47.5%-94.905% mannitol (95%x.999(mannitol if 1:999 ratio)=94.905%; 95%x.5(mannitol if 1:1 ratio)=47.5%)), respectively). The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain dry powder composition for inhalation that is inhalable and stable by formulating compound having Formula (A) as powder containing the compound having Formula (A) as the active and mannitol as a matrix former (as taught by Weiler) and obtain a dry powder that inhibits agglomeration by including L-leucine which is believed to concentrate on the surface to inhibit agglomeration (e.g., as taught by Mcintosh); and 2) determine the lowest effective dose with reduced chance of adverse effects by titrating the dose of the active over hours to days to achieve an effective dose with reduced chance of adverse effects (e.g., as taught by Therapeutics). The person of ordinary skill in the art would have reasonably expected success because Malinin discloses a method for treating pulmonary hypertension (PH) (column 7, lines 10-11) that includes pulmonary administration of a composition comprising the prostacyclin compound that is administered once daily to the patient via including a dry powder inhaler (column 7, lines 24-28). Malinin discloses treprostinil alkyl esters Formula (A):
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl) (column 51, lines 55-58; column 52, Formula (A); column 53, compound C16-TR). Malinin discloses inhaled C16-TR (e.g., R1 is hexadecyl) at a dose of 0.6-18 µg/kg for a rat (e.g., dose for 70 kg person is calculated to be about 6.8 µg to about 203.2 µg (human equivalent dose = dose of rat divided by 6.2) as evidenced by Sharma at Table 1 of Sharma) was well tolerated with no evidence of body weight and organ weight change after dosing for 14 consecutive days (column 82, lines 49-51). Malinin discloses dose of 6-90 µg/kg for dogs (e.g., dose for 70 kg person is calculated to be about 233.3 µg to about 3500 µg (human equivalent dose = dose of dog divided by 1.8) as evidenced by Sharma at Table 1 of Sharma) (column 81, lines 55-62). Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]). Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page).
Regarding claims 240-242, in light of the disclosure of Malinin and the teachings of Armer, it would have been prima facie obvious to treat pulmonary hypertension in a human by administering once daily a dose of a dry powder enclosed in a capsule that comprises a compound having the following formula:
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl), a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from 0.6-18 µg/kg (e.g. starting dose, titrated dose, and effective doses within 42 µg-1,260 µg (e.g., dose for 70 kg person; .6 µg x 70= 42 µg and 18 µg x 70 = 1,260 µg)); wherein the amount of the compound is 0.1-5 wt%, the amount of the hydrophobic amino acid including leucine is 10-70 wt% and the amount of the soluble carrier including mannitol is 25-89.9 wt%. Malinin discloses that the therapeutic response of the patient is including improved exercise capacity (e.g., as measured by the six-minute walk test) compared to pretreatment (column 42, lines 24-32). The method which is prima facie obvious in light of the disclosure of Malinin and the teachings of Weiler, Mcintosh and Therapeutics, is substantially the same as the instantly claimed method (e.g., same patient population of subjects with pulmonary hypertension that is administered the same drug in an effective amount that is in a dry powder and delivered by a dry powder inhaler). Therefore, the method which is prima facie obvious in light of the disclosure of Malinin and the teachings of Weiler, Mcintosh and Therapeutics necessarily has the same characteristics, e.g., improve exercise capacity of the subject during the administration period as measured by the six-minute walk distance by at least including about 5 meters during the administration period, compared to the patient’s distance walked in the six-minute walk distance prior to the administration period (e.g., claims 240-242), absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition is different from that taught by the prior art and to establish patentable differences. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Thus, the claimed invention as a whole is clearly prima facie obvious over the teachings of the prior art.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256, 260 and 262 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 9,469,600 (hereafter ‘600) in view of WEILER (WO 2010/060875 A1, publication date of 03 June 2010), MCINTOSH (US 2014/0294969 A1, THERAPEUTICS INITIATIVE (“Dose Titration: Minimize to Maximize”, October 1995; cited in PTO-892 mailed 03/01/2024; hereafter Therapeutics) and ROSCIGNO (US 2019/0151332 A1, effectively filing date of 05 November 2018).
Although the conflicting claims are not identical, they are not patentably distinct from each other because the claimed subject matter in the instant application is fully disclosed in the referenced US patent and would be covered by any patent granted on that referenced US patent.
Regarding instant claims 226, 229-230, 232, 235-239, claim 1 of ‘600 recites a prostacyclin compound of Formula (II):
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5. Claim 4 recites that n is 1. Therefore, the instant claims and the reference claims are drawn to identical compound with the same formula. The instant claims are drawn to a method of treating pulmonary hypertension in a patient comprising administering via a dry powder inhaler to the patient an effective amount of the compound during an administration period, wherein during administration period an initial dose of 80-160 µg of the compound is administered once daily in a single dosing session, and the initial dose is titrated to the patient’s highest tolerated dose. The referenced U.S. patent also disclosed (but did not claim) the compound as useful for treating pulmonary hypertension (PH), wherein WHO has classified PH into five groups (e.g., WHO Groups I-V (paragraph bridging columns 40 and 41)), and is administered via including a dry powder inhaler (column 1, lines 28-46; column 7, lines 27-46). The referenced U.S. patent also disclosed (but did not claim) that WHO Group III includes interstitial lung diseases and Group V includes sarcoidosis (paragraph bridging columns 40 and 41).
The referenced U.S. patent and the instant U.S. application are claiming a common subject matter, same compound of the same formula for use in treating pulmonary hypertension. For double patenting of previously disclosed, but newly claimed utility.
The referenced U.S. patent (‘600) does not specifically claim or disclose spray-dried dry powder composition consisting of spray-dried particles, wherein the spray-dried particles comprise: (i) from about 0.5 wt% to about 4 wt% of the treprostinil alkyl esters Formula (A) (e.g., Formula (I)), (ii) from about 29 wt% to about 61 wt% leucine, and (iii) the balance being mannitol, wherein the spray-dried powder composition does not contain DSPE-PEG2000. ‘600 does not specifically claim or disclose an initial dose of 80-160 µg of the compound and that the initial dose is titrated to the patient’s highest tolerated dose. The deficiencies are made up for by the teachings of Weiler, Mcintosh, Therapeutics and Roscigno.
Weiler is primarily directed towards powders for inhalation that are stable (see abstract and entire English translation of the patent publication).
Regarding claims 226 and 262, Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (e.g., .1% to 50% of the active ingredient; 100/1000=.1, 100/2= 50) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Therefore, Weiler teaches a spray-dried powder consisting of spry-dried particles that comprise active and mannitol that does not require DSPE-PEG2000 because Weiler teaches spray-dried powder that only requires an active and matrix former that includes mannitol (page 3, eighth paragraph and tenth paragraph; page 14, first paragraph; page 16, last paragraph).
Mcintosh is primarily directed towards dry powders for inhalation (abstract).
Regarding claim 226 and 262, Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]).
Therapeutics is primarily directed towards dose titration (see entire literature).
Regarding claims 226 and 245-247, Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page).
Roscigno is primarily directed towards a dry powder inhalation treatment for pulmonary arterial hypertension including a dose of dry particles comprising greater than 25 micrograms of Treprostinil in a capsule (abstract).
Regarding claims 226, 245, 249-250 and 256, Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]). Roscigno teaches that the patient is dosed including one time per day (e.g., a single dosing session once a day) (paragraph [0029]). Roscigno teaches that a dose of dry particles includes from about 75 micrograms to about 300 micrograms of treprostinil (paragraph [0028]).
Regarding claims 240-242, Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]).
Regarding claim 254, Roscigno teaches providing the patient at least one capsule for use in the dry powder inhaler (paragraph [0029]).
Regarding claim 255, Roscigno teaches that the patient is dosed including one time per day and including greater than or equal to 200 micrograms of Treprostinil to a patient per breath (e.g. one inhalation for one session per day) (paragraph [0029]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses) ; wherein the spray-dried powder contains matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1; and wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight (e.g., the amount of the active and matrix former (e.g., mannitol) is calculated to range from 0.05%-47.5% and 25%-94.905% (example of calculations: for 5% leucine, 95% of dry powder left and using ratio range of 1:999 to 1:1 taught by Weiler gives .095%-47.5% active (95%x.001(active if 1:999 ratio)=.095%; 95%x.5 (active if 1:1 ratio)) and 47.5%-94.905% mannitol (95%x.999(mannitol if 1:999 ratio)=94.905%; 95%x.5(mannitol if 1:1 ratio)=47.5%)), respectively). The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain dry powder composition for inhalation that is inhalable and stable by formulating compound having Formula (A) as powder containing the compound having Formula (A) as the active and mannitol as a matrix former (as taught by Weiler) and obtain a dry powder that inhibits agglomeration by including L-leucine which is believed to concentrate on the surface to inhibit agglomeration (e.g., as taught by Mcintosh); 2) determine an effective dose for the subject and with minimum systemic exposure by titrating the dose as taught by Therapeutics; and used amounts of including greater than 25 micrograms as taught by Roscigno. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘600 recites a prostacyclin compound of Formula (II):
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5. Claim 4 recites that n is 1. ‘600 also disclosed (but did not claim) the compound as useful for treating pulmonary hypertension and is administered via including a dry powder inhaler (column 1, lines 28-46; column 7, lines 27-46). Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]). Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page). Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]).
Regarding claims 240-242, in light of the disclosure of claims and disclosure of ‘600 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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,
wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses); wherein the amount of the compound is 0.1-5 wt%, the amount of the hydrophobic amino acid including leucine is 10-70 wt% and the amount of the soluble carrier including mannitol is 25-89.9 wt%. Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]). The method which is prima facie obvious in light of the claims and disclosure of ‘600 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, is substantially the same as the instantly claimed method (e.g., same patient population of subjects with pulmonary hypertension that is administered the same drug in an effective amount that is in a dry powder and delivered by a dry powder inhaler), therefore, the method which is prima facie obvious in light of the claims and disclosure of ‘600 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno necessarily has the same characteristics, e.g., improve exercise capacity of the subject during the administration period as measured by the six-minute walk distance (e.g., claims 240-242), absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition is different from that taught by the prior art and to establish patentable differences. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256, 260 and 262 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 9,255,064 (hereafter ‘064) in view of WEILER (WO 2010/060875 A1, publication date of 03 June 2010), MCINTOSH (US 2014/0294969 A1, THERAPEUTICS INITIATIVE (“Dose Titration: Minimize to Maximize”, October 1995; cited in PTO-892 mailed 03/01/2024; hereafter Therapeutics) and ROSCIGNO (US 2019/0151332 A1, effectively filing date of 05 November 2018).
Although the conflicting claims are not identical, they are not patentably distinct from each other because the claimed subject matter in the instant application is fully disclosed in the referenced US patent and would be covered by any patent granted on that referenced US patent.
Regarding instant claims 226, 229-230, 232, 235-239, claim 1 of ‘064 recites a prostacyclin compound of Formula (II):
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5. Claim 4 recites that n is 1. Therefore, the instant claims and the reference claims are drawn to identical compound with the same formula. The instant claims are drawn to a method of treating pulmonary hypertension in a patient comprising administering via a dry powder inhaler to the patient an effective amount of the compound during an administration period, wherein during administration period an initial dose of 80-160 µg of the compound is administered once daily in a single dosing session, and the initial dose is titrated to the patient’s highest tolerated dose. The referenced U.S. patent also disclosed (but did not claim) the compound as useful for treating pulmonary hypertension (PH), wherein WHO has classified PH into five groups (e.g., WHO Groups I-V (paragraph bridging columns 39 and 40)), and is administered via including a dry powder inhaler (column 1, lines 29-48; column 7, lines 10-28). The referenced U.S. patent also disclosed (but did not claim) that WHO Group III includes interstitial lung diseases and Group V includes sarcoidosis (paragraph bridging columns 40 and 41).
The referenced U.S. patent and the instant U.S. application are claiming a common subject matter, same compound of the same formula for use in treating pulmonary hypertension. For double patenting of previously disclosed, but newly claimed utility.
The referenced U.S. patent (‘064) does not specifically claim or disclose spray-dried dry powder composition consisting of spray-dried particles, wherein the spray-dried particles comprise: (i) from about 0.5 wt% to about 4 wt% of the treprostinil alkyl esters Formula (A) (e.g., Formula (I)), (ii) from about 29 wt% to about 61 wt% leucine, and (iii) the balance being mannitol, wherein the spray-dried powder composition does not contain DSPE-PEG2000. ‘064 does not specifically claim or disclose an initial dose of 80-160 µg of the compound and that the initial dose is titrated to the patient’s highest tolerated dose. The deficiencies are made up for by the teachings of Weiler, Mcintosh, Therapeutics and Roscigno.
Weiler is primarily directed towards powders for inhalation that are stable (see abstract and entire English translation of the patent publication).
Regarding claims 226 and 262, Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (e.g., .1% to 50% of the active ingredient; 100/1000=.1, 100/2= 50) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Therefore, Weiler teaches a spray-dried powder consisting of spry-dried particles that comprise active and mannitol that does not require DSPE-PEG2000 because Weiler teaches spray-dried powder that only requires an active and matrix former that includes mannitol (page 3, eighth paragraph and tenth paragraph; page 14, first paragraph; page 16, last paragraph).
Mcintosh is primarily directed towards dry powders for inhalation (abstract).
Regarding claim 226 and 262, Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]).
Therapeutics is primarily directed towards dose titration (see entire literature).
Regarding claims 226 and 245-247, Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page).
Roscigno is primarily directed towards a dry powder inhalation treatment for pulmonary arterial hypertension including a dose of dry particles comprising greater than 25 micrograms of Treprostinil in a capsule (abstract).
Regarding claims 226, 245, 249-250 and 256, Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]). Roscigno teaches that the patient is dosed including one time per day (e.g., a single dosing session once a day) (paragraph [0029]). Roscigno teaches that a dose of dry particles includes from about 75 micrograms to about 300 micrograms of treprostinil (paragraph [0028]).
Regarding claims 240-242, Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]).
Regarding claim 254, Roscigno teaches providing the patient at least one capsule for use in the dry powder inhaler (paragraph [0029]).
Regarding claim 255, Roscigno teaches that the patient is dosed including one time per day and including greater than or equal to 200 micrograms of Treprostinil to a patient per breath (e.g. one inhalation for one session per day) (paragraph [0029]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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,
wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses) ; wherein the spray-dried powder contains matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1; and wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight (e.g., the amount of the active and matrix former (e.g., mannitol) is calculated to range from 0.05%-47.5% and 25%-94.905% (example of calculations: for 5% leucine, 95% of dry powder left and using ratio range of 1:999 to 1:1 taught by Weiler gives .095%-47.5% active (95%x.001(active if 1:999 ratio)=.095%; 95%x.5 (active if 1:1 ratio)) and 47.5%-94.905% mannitol (95%x.999(mannitol if 1:999 ratio)=94.905%; 95%x.5(mannitol if 1:1 ratio)=47.5%)), respectively). The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain dry powder composition for inhalation that is inhalable and stable by formulating compound having Formula (A) as powder containing the compound having Formula (A) as the active and mannitol as a matrix former (as taught by Weiler) and obtain a dry powder that inhibits agglomeration by including L-leucine which is believed to concentrate on the surface to inhibit agglomeration (e.g., as taught by Mcintosh); 2) determine an effective dose for the subject and with minimum systemic exposure by titrating the dose as taught by Therapeutics; and used amounts of including greater than 25 micrograms as taught by Roscigno. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘064 recites a prostacyclin compound of Formula (II):
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414
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5. Claim 4 recites that n is 1. Therefore, the instant claims and the reference claims are drawn to identical compound with the same formula. The referenced U.S. patent also disclosed (but did not claim) the compound as useful for treating pulmonary hypertension (PH), wherein WHO has classified PH into five groups (e.g., WHO Groups I-V (paragraph bridging columns 39 and 40)), and is administered via including a dry powder inhaler (column 1, lines 29-48; column 7, lines 10-28). The referenced U.S. patent also disclosed (but did not claim) that WHO Group III includes interstitial lung diseases and Group V includes sarcoidosis (paragraph bridging columns 40 and 41). Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]). Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page). Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]).
Regarding claims 240-242, in light of the disclosure of claims and disclosure of ‘064 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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,
wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses); wherein the amount of the compound is 0.1-5 wt%, the amount of the hydrophobic amino acid including leucine is 10-70 wt% and the amount of the soluble carrier including mannitol is 25-89.9 wt%. Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]). The method which is prima facie obvious in light of the claims and disclosure of ‘064 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, is substantially the same as the instantly claimed method (e.g., same patient population of subjects with pulmonary hypertension that is administered the same drug in an effective amount that is in a dry powder and delivered by a dry powder inhaler), therefore, the method which is prima facie obvious in light of the claims and disclosure of ‘064 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno necessarily has the same characteristics, e.g., improve exercise capacity of the subject during the administration period as measured by the six-minute walk distance (e.g., claims 240-242), absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition is different from that taught by the prior art and to establish patentable differences. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256, 260 and 262 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 17 of U.S. Patent No. 10,010,518 (hereafter ‘518) in view of WEILER (WO 2010/060875 A1, publication date of 03 June 2010), MCINTOSH (US 2014/0294969 A1, THERAPEUTICS INITIATIVE (“Dose Titration: Minimize to Maximize”, October 1995; cited in PTO-892 mailed 03/01/2024; hereafter Therapeutics) and ROSCIGNO (US 2019/0151332 A1, effectively filing date of 05 November 2018).
Regarding instant claims 226, 229-230, 232, 235-236, claim 1 of ‘518 recites a method of treating pulmonary hypertension in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising effective amount of a compound of Formula (II):
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5. Claims 2-6 of ‘518 recites the patient is a WHO Group I-V PH patient, respectively. Claim 7 of ‘518 recites administration via including a dry powder inhaler. Claim 8 of ‘518 recites that the PH is pulmonary arterial hypertension (PAH). Claim 17 of ‘518 recites administration once daily.
The referenced U.S. patent (‘518) does not specifically claim or disclose spray-dried dry powder composition consisting of spray-dried particles, wherein the spray-dried particles comprise: (i) from about 0.5 wt% to about 4 wt% of the treprostinil alkyl esters Formula (A) (e.g., Formula (I)), (ii) from about 29 wt% to about 61 wt% leucine, and (iii) the balance being mannitol, wherein the spray-dried powder composition does not contain DSPE-PEG2000. ‘518 does not specifically claim or disclose an initial dose of 80-160 µg of the compound and that the initial dose is titrated to the patient’s highest tolerated dose. The deficiencies are made up for by the teachings of Weiler, Mcintosh, Therapeutics and Roscigno.
Weiler is primarily directed towards powders for inhalation that are stable (see abstract and entire English translation of the patent publication).
Regarding claims 226 and 262, Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (e.g., .1% to 50% of the active ingredient; 100/1000=.1, 100/2= 50) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Therefore, Weiler teaches a spray-dried powder consisting of spry-dried particles that comprise active and mannitol that does not require DSPE-PEG2000 because Weiler teaches spray-dried powder that only requires an active and matrix former that includes mannitol (page 3, eighth paragraph and tenth paragraph; page 14, first paragraph; page 16, last paragraph).
Mcintosh is primarily directed towards dry powders for inhalation (abstract).
Regarding claim 226 and 262, Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]).
Therapeutics is primarily directed towards dose titration (see entire literature).
Regarding claims 226 and 245-247, Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page).
Roscigno is primarily directed towards a dry powder inhalation treatment for pulmonary arterial hypertension including a dose of dry particles comprising greater than 25 micrograms of Treprostinil in a capsule (abstract).
Regarding claims 226, 245, 249-250 and 256, Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]). Roscigno teaches that the patient is dosed including one time per day (e.g., a single dosing session once a day) (paragraph [0029]). Roscigno teaches that a dose of dry particles includes from about 75 micrograms to about 300 micrograms of treprostinil (paragraph [0028]).
Regarding claims 240-242, Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]).
Regarding claim 254, Roscigno teaches providing the patient at least one capsule for use in the dry powder inhaler (paragraph [0029]).
Regarding claim 255, Roscigno teaches that the patient is dosed including one time per day and including greater than or equal to 200 micrograms of Treprostinil to a patient per breath (e.g. one inhalation for one session per day) (paragraph [0029]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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386
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,
wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses) ; wherein the spray-dried powder contains matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1; and wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight (e.g., the amount of the active and matrix former (e.g., mannitol) is calculated to range from 0.05%-47.5% and 25%-94.905% (example of calculations: for 5% leucine, 95% of dry powder left and using ratio range of 1:999 to 1:1 taught by Weiler gives .095%-47.5% active (95%x.001(active if 1:999 ratio)=.095%; 95%x.5 (active if 1:1 ratio)) and 47.5%-94.905% mannitol (95%x.999(mannitol if 1:999 ratio)=94.905%; 95%x.5(mannitol if 1:1 ratio)=47.5%)), respectively). The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain dry powder composition for inhalation that is inhalable and stable by formulating compound having Formula (A) as powder containing the compound having Formula (A) as the active and mannitol as a matrix former (as taught by Weiler) and obtain a dry powder that inhibits agglomeration by including L-leucine which is believed to concentrate on the surface to inhibit agglomeration (e.g., as taught by Mcintosh); 2) determine an effective dose for the subject and with minimum systemic exposure by titrating the dose as taught by Therapeutics; and used amounts of including greater than 25 micrograms as taught by Roscigno. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘518 recites a method of treating pulmonary hypertension in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising effective amount of a compound of Formula (II):
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414
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5. Claims 2-6 of ‘518 recites the patient is a WHO Group I-V PH patient, respectively. Claim 7 of ‘518 recites administration via including a dry powder inhaler. Claim 8 of ‘518 recites that the PH is pulmonary arterial hypertension (PAH). Claim 17 of ‘518 recites administration once daily. Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]). Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page). Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]).
Regarding claims 240-242, in light of the disclosure of claims and disclosure of ‘518 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses); wherein the amount of the compound is 0.1-5 wt%, the amount of the hydrophobic amino acid including leucine is 10-70 wt% and the amount of the soluble carrier including mannitol is 25-89.9 wt%. Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]). The method which is prima facie obvious in light of the claims and disclosure of ‘518 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, is substantially the same as the instantly claimed method (e.g., same patient population of subjects with pulmonary hypertension that is administered the same drug in an effective amount that is in a dry powder and delivered by a dry powder inhaler), therefore, the method which is prima facie obvious in light of the claims and disclosure of ‘518 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno necessarily has the same characteristics, e.g., improve exercise capacity of the subject during the administration period as measured by the six-minute walk distance (e.g., claims 240-242), absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition is different from that taught by the prior art and to establish patentable differences. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256, 260 and 262 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 10,526,274 (hereafter ‘274) in view of WEILER (WO 2010/060875 A1, publication date of 03 June 2010), MCINTOSH (US 2014/0294969 A1, THERAPEUTICS INITIATIVE (“Dose Titration: Minimize to Maximize”, October 1995; cited in PTO-892 mailed 03/01/2024; hereafter Therapeutics) and ROSCIGNO (US 2019/0151332 A1, effectively filing date of 05 November 2018).
Regarding instant claims 226, 229-230, 232 and 237-238, claim 1 of ‘274 recites a method of treating pulmonary fibrosis (e.g., a species pulmonary hypertension) in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising effective amount of a compound of Formula (II):
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5. Claims 2 and 10 of ‘274 recites administration via including a dry powder inhaler. Claim 3 of ‘274 recites administration once daily.
The referenced U.S. patent (‘274) does not specifically claim or disclose spray-dried dry powder composition consisting of spray-dried particles, wherein the spray-dried particles comprise: (i) from about 0.5 wt% to about 4 wt% of the treprostinil alkyl esters Formula (A) (e.g., Formula (I)), (ii) from about 29 wt% to about 61 wt% leucine, and (iii) the balance being mannitol, wherein the spray-dried powder composition does not contain DSPE-PEG2000. ‘274 does not specifically claim or disclose an initial dose of 80-160 µg of the compound and that the initial dose is titrated to the patient’s highest tolerated dose. The deficiencies are made up for by the teachings of Weiler, Mcintosh, Therapeutics and Roscigno.
Weiler is primarily directed towards powders for inhalation that are stable (see abstract and entire English translation of the patent publication).
Regarding claims 226 and 262, Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (e.g., .1% to 50% of the active ingredient; 100/1000=.1, 100/2= 50) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Therefore, Weiler teaches a spray-dried powder consisting of spry-dried particles that comprise active and mannitol that does not require DSPE-PEG2000 because Weiler teaches spray-dried powder that only requires an active and matrix former that includes mannitol (page 3, eighth paragraph and tenth paragraph; page 14, first paragraph; page 16, last paragraph).
Mcintosh is primarily directed towards dry powders for inhalation (abstract).
Regarding claim 226 and 262, Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]).
Therapeutics is primarily directed towards dose titration (see entire literature).
Regarding claims 226 and 245-247, Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page).
Roscigno is primarily directed towards a dry powder inhalation treatment for pulmonary arterial hypertension including a dose of dry particles comprising greater than 25 micrograms of Treprostinil in a capsule (abstract).
Regarding claims 226, 245, 249-250 and 256, Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]). Roscigno teaches that the patient is dosed including one time per day (e.g., a single dosing session once a day) (paragraph [0029]). Roscigno teaches that a dose of dry particles includes from about 75 micrograms to about 300 micrograms of treprostinil (paragraph [0028]).
Regarding claims 230, 232 and 235-239, Roscigno teaches pulmonary hypertension is divided into five groups based on WHO criteria that is designated as WHO Groups 1 through 5 (paragraph [0005]).
Regarding claims 240-242, Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]).
Regarding claim 254, Roscigno teaches providing the patient at least one capsule for use in the dry powder inhaler (paragraph [0029]).
Regarding claim 255, Roscigno teaches that the patient is dosed including one time per day and including greater than or equal to 200 micrograms of Treprostinil to a patient per breath (e.g. one inhalation for one session per day) (paragraph [0029]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses) ; wherein the spray-dried powder contains matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1; and wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight (e.g., the amount of the active and matrix former (e.g., mannitol) is calculated to range from 0.05%-47.5% and 25%-94.905% (example of calculations: for 5% leucine, 95% of dry powder left and using ratio range of 1:999 to 1:1 taught by Weiler gives .095%-47.5% active (95%x.001(active if 1:999 ratio)=.095%; 95%x.5 (active if 1:1 ratio)) and 47.5%-94.905% mannitol (95%x.999(mannitol if 1:999 ratio)=94.905%; 95%x.5(mannitol if 1:1 ratio)=47.5%)), respectively). The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain dry powder composition for inhalation that is inhalable and stable by formulating compound having Formula (A) as powder containing the compound having Formula (A) as the active and mannitol as a matrix former (as taught by Weiler) and obtain a dry powder that inhibits agglomeration by including L-leucine which is believed to concentrate on the surface to inhibit agglomeration (e.g., as taught by Mcintosh); 2) determine an effective dose for the subject and with minimum systemic exposure by titrating the dose as taught by Therapeutics; and used amounts of including greater than 25 micrograms as taught by Roscigno. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘274 recites a method of treating pulmonary fibrosis (e.g., a species pulmonary hypertension) in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising effective amount of a compound of Formula (II):
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5. Claims 2 and 10 of ‘274 recites administration via including a dry powder inhaler. Claim 3 of ‘274 recites administration once daily. Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]). Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page). Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]).
Regarding claims 240-242, in light of the disclosure of claims and disclosure of ‘274 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses); wherein the amount of the compound is 0.1-5 wt%, the amount of the hydrophobic amino acid including leucine is 10-70 wt% and the amount of the soluble carrier including mannitol is 25-89.9 wt%. Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]). The method which is prima facie obvious in light of the claims and disclosure of ‘274 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, is substantially the same as the instantly claimed method (e.g., same patient population of subjects with pulmonary hypertension that is administered the same drug in an effective amount that is in a dry powder and delivered by a dry powder inhaler), therefore, the method which is prima facie obvious in light of the claims and disclosure of ‘274 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno necessarily has the same characteristics, e.g., improve exercise capacity of the subject during the administration period as measured by the six-minute walk distance (e.g., claims 240-242), absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition is different from that taught by the prior art and to establish patentable differences. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256, 260 and 262 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23 and 25 of U.S. Patent No. 10,995,055 (hereafter ‘055) in view of WEILER (WO 2010/060875 A1, publication date of 03 June 2010), MCINTOSH (US 2014/0294969 A1, THERAPEUTICS INITIATIVE (“Dose Titration: Minimize to Maximize”, October 1995; cited in PTO-892 mailed 03/01/2024; hereafter Therapeutics) and ROSCIGNO (US 2019/0151332 A1, effectively filing date of 05 November 2018).
Regarding instant claims 226, 229-230 and 235-236, claim 23 of ‘055 recites a method of treating pulmonary hypertension in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising effective amount of a compound of Formula (II):
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wherein R1 is O; R2 is including linear hexadecyl; and n is an integer from 0 to 5, wherein the composition is in the form of a dry powder, wherein the administration is carried out via a dry powder inhaler. Claim 25 of ‘055 recites that the PH is pulmonary arterial hypertension (PAH).
The referenced U.S. patent (‘055) does not specifically claim or disclose spray-dried dry powder composition consisting of spray-dried particles, wherein the spray-dried particles comprise: (i) from about 0.5 wt% to about 4 wt% of the treprostinil alkyl esters Formula (A) (e.g., Formula (I)), (ii) from about 29 wt% to about 61 wt% leucine, and (iii) the balance being mannitol, wherein the spray-dried powder composition does not contain DSPE-PEG2000. ‘055 does not specifically claim or disclose an initial dose of 80-160 µg of the compound and that the initial dose is titrated to the patient’s highest tolerated dose. The deficiencies are made up for by the teachings of Weiler, Mcintosh, Therapeutics and Roscigno.
Weiler is primarily directed towards powders for inhalation that are stable (see abstract and entire English translation of the patent publication).
Regarding claims 226 and 262, Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (e.g., .1% to 50% of the active ingredient; 100/1000=.1, 100/2= 50) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Therefore, Weiler teaches a spray-dried powder consisting of spry-dried particles that comprise active and mannitol that does not require DSPE-PEG2000 because Weiler teaches spray-dried powder that only requires an active and matrix former that includes mannitol (page 3, eighth paragraph and tenth paragraph; page 14, first paragraph; page 16, last paragraph).
Mcintosh is primarily directed towards dry powders for inhalation (abstract).
Regarding claim 226 and 262, Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]).
Therapeutics is primarily directed towards dose titration (see entire literature).
Regarding claims 226 and 245-247, Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page).
Roscigno is primarily directed towards a dry powder inhalation treatment for pulmonary arterial hypertension including a dose of dry particles comprising greater than 25 micrograms of Treprostinil in a capsule (abstract).
Regarding claims 226, 245, 249-250 and 256, Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]). Roscigno teaches that the patient is dosed including one time per day (e.g., a single dosing session once a day) (paragraph [0029]). Roscigno teaches that a dose of dry particles includes from about 75 micrograms to about 300 micrograms of treprostinil (paragraph [0028]).
Regarding claims 230, 232 and 235-239, Roscigno teaches pulmonary hypertension is divided into five groups based on WHO criteria that is designated as WHO Groups 1 through 5 (paragraph [0005]).
Regarding claims 240-242, Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]).
Regarding claim 254, Roscigno teaches providing the patient at least one capsule for use in the dry powder inhaler (paragraph [0029]).
Regarding claim 255, Roscigno teaches that the patient is dosed including one time per day and including greater than or equal to 200 micrograms of Treprostinil to a patient per breath (e.g. one inhalation for one session per day) (paragraph [0029]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses) ; wherein the spray-dried powder contains matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1; and wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight (e.g., the amount of the active and matrix former (e.g., mannitol) is calculated to range from 0.05%-47.5% and 25%-94.905% (example of calculations: for 5% leucine, 95% of dry powder left and using ratio range of 1:999 to 1:1 taught by Weiler gives .095%-47.5% active (95%x.001(active if 1:999 ratio)=.095%; 95%x.5 (active if 1:1 ratio)) and 47.5%-94.905% mannitol (95%x.999(mannitol if 1:999 ratio)=94.905%; 95%x.5(mannitol if 1:1 ratio)=47.5%)), respectively). The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain dry powder composition for inhalation that is inhalable and stable by formulating compound having Formula (A) as powder containing the compound having Formula (A) as the active and mannitol as a matrix former (as taught by Weiler) and obtain a dry powder that inhibits agglomeration by including L-leucine which is believed to concentrate on the surface to inhibit agglomeration (e.g., as taught by Mcintosh); 2) determine an effective dose for the subject and with minimum systemic exposure by titrating the dose as taught by Therapeutics; and used amounts of including greater than 25 micrograms as taught by Roscigno. The person of ordinary skill in the art would have reasonably expected success because claim 23 of ‘055 recites a method of treating pulmonary hypertension in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising effective amount of a compound of Formula (II):
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wherein R1 is O; R2 is including linear hexadecyl; and n is an integer from 0 to 5, wherein the composition is in the form of a dry powder, wherein the administration is carried out via a dry powder inhaler. Claim 25 of ‘055 recites that the PH is pulmonary arterial hypertension (PAH). Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]). Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page). Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]).
Regarding claims 240-242, in light of the disclosure of claims and disclosure of ‘055 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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,
wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses); wherein the amount of the compound is 0.1-5 wt%, the amount of the hydrophobic amino acid including leucine is 10-70 wt% and the amount of the soluble carrier including mannitol is 25-89.9 wt%. Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]). The method which is prima facie obvious in light of the claims and disclosure of ‘055 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, is substantially the same as the instantly claimed method (e.g., same patient population of subjects with pulmonary hypertension that is administered the same drug in an effective amount that is in a dry powder and delivered by a dry powder inhaler), therefore, the method which is prima facie obvious in light of the claims and disclosure of ‘055 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno necessarily has the same characteristics, e.g., improve exercise capacity of the subject during the administration period as measured by the six-minute walk distance (e.g., claims 240-242), absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition is different from that taught by the prior art and to establish patentable differences. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256, 260 and 262 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 11,795,135 (hereafter ‘135) in view of WEILER (WO 2010/060875 A1, publication date of 03 June 2010), MCINTOSH (US 2014/0294969 A1,THERAPEUTICS INITIATIVE (“Dose Titration: Minimize to Maximize”, October 1995; cited in PTO-892 mailed 03/01/2024; hereafter Therapeutics) and ROSCIGNO (US 2019/0151332 A1, effectively filing date of 05 November 2018).
Regarding instant claims 226, 229, 232 and 237-238, claim 1 of ‘135 recites a method of treating pulmonary hypertension associated with interstitial lung disease in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising effective amount of a compound of Formula (II):
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5, wherein the composition is in the form of a dry powder, wherein the administration is carried out via a dry powder inhaler. Claim 2 recites that the patient is a WHO Group III PH patient.
The referenced U.S. patent (‘135) does not specifically claim or disclose spray-dried dry powder composition consisting of spray-dried particles, wherein the spray-dried particles comprise: (i) from about 0.5 wt% to about 4 wt% of the treprostinil alkyl esters Formula (A) (e.g., Formula (I)), (ii) from about 29 wt% to about 61 wt% leucine, and (iii) the balance being mannitol, wherein the spray-dried powder composition does not contain DSPE-PEG2000. ‘135 does not specifically claim or disclose an initial dose of 80-160 µg of the compound and that the initial dose is titrated to the patient’s highest tolerated dose. The deficiencies are made up for by the teachings of Weiler, Mcintosh, Therapeutics and Roscigno.
Weiler is primarily directed towards powders for inhalation that are stable (see abstract and entire English translation of the patent publication).
Regarding claims 226 and 262, Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (e.g., .1% to 50% of the active ingredient; 100/1000=.1, 100/2= 50) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Therefore, Weiler teaches a spray-dried powder consisting of spry-dried particles that comprise active and mannitol that does not require DSPE-PEG2000 because Weiler teaches spray-dried powder that only requires an active and matrix former that includes mannitol (page 3, eighth paragraph and tenth paragraph; page 14, first paragraph; page 16, last paragraph).
Mcintosh is primarily directed towards dry powders for inhalation (abstract).
Regarding claim 226 and 262, Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]).
Therapeutics is primarily directed towards dose titration (see entire literature).
Regarding claims 226 and 245-247, Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page).
Roscigno is primarily directed towards a dry powder inhalation treatment for pulmonary arterial hypertension including a dose of dry particles comprising greater than 25 micrograms of Treprostinil in a capsule (abstract).
Regarding claims 226, 245, 249-250 and 256, Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]). Roscigno teaches that the patient is dosed including one time per day (e.g., a single dosing session once a day) (paragraph [0029]). Roscigno teaches that a dose of dry particles includes from about 75 micrograms to about 300 micrograms of treprostinil (paragraph [0028]).
Regarding claims 230, 232 and 235-239, Roscigno teaches pulmonary hypertension is divided into five groups based on WHO criteria that is designated as WHO Groups 1 through 5 (paragraph [0005]).
Regarding claims 240-242, Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]).
Regarding claim 254, Roscigno teaches providing the patient at least one capsule for use in the dry powder inhaler (paragraph [0029]).
Regarding claim 255, Roscigno teaches that the patient is dosed including one time per day and including greater than or equal to 200 micrograms of Treprostinil to a patient per breath (e.g. one inhalation for one session per day) (paragraph [0029]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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,
wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses) ; wherein the spray-dried powder contains matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1; and wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight (e.g., the amount of the active and matrix former (e.g., mannitol) is calculated to range from 0.05%-47.5% and 25%-94.905% (example of calculations: for 5% leucine, 95% of dry powder left and using ratio range of 1:999 to 1:1 taught by Weiler gives .095%-47.5% active (95%x.001(active if 1:999 ratio)=.095%; 95%x.5 (active if 1:1 ratio)) and 47.5%-94.905% mannitol (95%x.999(mannitol if 1:999 ratio)=94.905%; 95%x.5(mannitol if 1:1 ratio)=47.5%)), respectively). The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain dry powder composition for inhalation that is inhalable and stable by formulating compound having Formula (A) as powder containing the compound having Formula (A) as the active and mannitol as a matrix former (as taught by Weiler) and obtain a dry powder that inhibits agglomeration by including L-leucine which is believed to concentrate on the surface to inhibit agglomeration (e.g., as taught by Mcintosh); 2) determine an effective dose for the subject and with minimum systemic exposure by titrating the dose as taught by Therapeutics; and used amounts of including greater than 25 micrograms as taught by Roscigno. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘135 recites a method of treating pulmonary hypertension associated with interstitial lung disease in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising effective amount of a compound of Formula (II):
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247
414
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wherein R1 is O; R2 is including hexadecyl; and n is an integer from 0 to 5, wherein the composition is in the form of a dry powder, wherein the administration is carried out via a dry powder inhaler. Claim 2 recites that the patient is a WHO Group III PH patient. Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]). Therapeutics teaches starting with the lowest available dose and titration should occur over hours to days to achieve an effective dose with reduced chance of adverse effects (paragraph bridging the first and second page). Roscigno teaches an inhalation dry powder formulation of treprostinil. Roscigno teaches that the dry powder comprises including greater than 25 micrograms of treprostinil (paragraph [0028]).
Regarding claims 240-242, in light of the disclosure of claims and disclosure of ‘135 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary hypertension in a human by administering a dry powder enclosed in a capsule once daily that comprises a compound having structure II:
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386
647
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,
wherein R1 is O; R2 is including hexadecyl; and n is an integer including 1, a hydrophobic amino acid including leucine, and a soluble carrier including mannitol; titrating the dose of the compound to higher doses over hours to days to determine an effective dose of the compound with reduced chance of adverse effects; wherein the dose of the compound includes from about 75 micrograms to about 300 micrograms (e.g., starting dose, titrated dose, and effective doses); wherein the amount of the compound is 0.1-5 wt%, the amount of the hydrophobic amino acid including leucine is 10-70 wt% and the amount of the soluble carrier including mannitol is 25-89.9 wt%. Roscigno teaches that treatment pulmonary arterial hypertension include improvement in the 6 minute walk distance (paragraph [0011]). The method which is prima facie obvious in light of the claims and disclosure of ‘135 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno, is substantially the same as the instantly claimed method (e.g., same patient population of subjects with pulmonary hypertension that is administered the same drug in an effective amount that is in a dry powder and delivered by a dry powder inhaler), therefore, the method which is prima facie obvious in light of the claims and disclosure of ‘135 and the teachings of Weiler, Mcintosh, Therapeutics and Roscigno necessarily has the same characteristics, e.g., improve exercise capacity of the subject during the administration period as measured by the six-minute walk distance (e.g., claims 240-242), absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition is different from that taught by the prior art and to establish patentable differences. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Response to Arguments
Applicant’s arguments will be addressed as they pertain to the new grounds of rejection above. Applicant argues that the Weers Declaration is relevant for combination of references cited because the Weers Declaration states that formulation and manufacturing process of one API will not necessarily work for a second API because the different physical and chemical properties of the API, such as API solubility, results in different interactions with carriers and other components.
Applicant's arguments filed on 15 June 2026 and the Weers Declaration have been fully considered but they are not persuasive. In response, Malinin a composition comprising a prostacyclin compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for including pulmonary administration to treat pulmonary hypertension (PH) (column 7, lines 10-11; 7, lines 24-28). Malinin discloses specifically a treprostinil alkyl esters Formula (A):
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320
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl) (column 51, lines 55-58; column 52, Formula (A); column 53, compound C16-TR). Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]). Therefore, in light of the disclosure of Malinin and the teachings of Weiler and Mcintosh, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a capsule (e.g., contains a shell) for inhalation that is filled with a dry powder for inhalation that is produced by spray drying that comprises a compound having the following formula:
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500
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl), water-matrix former including mannitol, and L-leucine; wherein the ratio of the compound having Formula (A) to matrix former is in a concentration such that the ratio of the compound having Formula (A):matrix former is 1:999 to 1:1 (w/w); wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight; and wherein the dose of the compound having Formula (A) includes from 0.6-18 µg/kg for a rat (e.g., dose for 70 kg person is calculated to be about 6.8 µg to about 203.2 µg (human equivalent dose = dose of rat divided by 6.2)) and 6-90 µg/kg for dogs (e.g., dose for 70 kg person is calculated to be about 233.3 µg to about 3500 µg (human equivalent dose = dose of dog divided by 1.8) as evidenced by Sharma at Table 1 of Sharma).
Applicant is reminded that obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). See MPEP 2143.02(II).
Regarding the Weers Declaration and arguments about different drugs having different properties so the formulation and manufacturing process of one API will not necessarily work for a second API, no factual evidence has been provided. The Weers Declaration and arguments are considered conclusory opinion without factual evidence that show nonobviousness. In light of the disclosure of Malinin and the teachings of Weiler and Mcintosh (described above), there is a reasonable expectation of success that the compound having Formula (A) of Malinin can be produced as a spray dried powder of Weiler which contains an active and a matrix former including mannitol and further include L-leucine to further provide inhibiting of agglomeration of the dry powder, as taught by Mcintosh.
The rest of the remaining arguments with respect to claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256 and 262 have been considered but are moot because the new grounds of rejection relies on a different combination of references.
Thus, for the reasons of record and for the reasons presented above claims 226, 229-230, 232, 235-242, 245-247, 249-250, 254-256 and 262 are rejected under 35 U.S.C. 103(a) and on the ground of nonstatutory double patenting.
Conclusion and Correspondence
No claims are allowed.
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/JOHN P NGUYEN/
Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600
