DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of hydrogenated soy phosphatidylcholine and distearyloyl phosphatidylglycerol in the reply filed on 07/08/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Objections
Claims 33 and 37 are objected to because of the following informalities:
Claim 33 and 37 respectively recite “PEF-DSPE” and “DOPG” without previously reciting the chemical name. This is considered a minor informality because it is not congruent with how the phospholipids are recited in the rest of the claims. “PEF-DSPE” is understood to mean 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (see specification at p. 6, line 8). “DOPG” is understood to mean 1,2-dioleoyl-sn-glycero-3-phosphoglycerol, as evidenced by BroadPharm (DOPG, 2026 [retrieved 07/29/2026], https://broadpharm.com/product/bp-26300).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 47 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “formulated for” in claim 47 is a relative term which renders the claim indefinite. The term “formulated for” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what is meant by this term such that the artisan would reasonably appreciate the metes and bound of what is encompassed by it. It is not clear what specific limitations are imposed on a composition “formulated for” inhalation and so it is not clear how far from the base composition one can deviate and still meet the requirements of the claim. For the purposes of examination, “formulated for” will be interpreted as “capable of”.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1) Claims 25-41, 43, 45, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Gessler et al. (Therapeutic Advances in Respiratory Disease, 2011, v. 5, no. 3, p. 195-206) in view of Pilkiewicz et al. (WO 2000/27359, publication date 05/18/2000), Hariharan et a. (Clinical Pharmacology and Biopharmaceutics Reviews; 203496Orig1s000, 2011), Clerc et al. (US 5,939,096, date of patent 08/17/1999), and Chountoulesi et al. (Journal of Liposome Research, 2018 (published online 06/06/2017), v. 28, no. 3, p. 249-258).
Gessler discloses that “[i]nhaled treprostinil is a safe and well-tolerated approved pharmaceutical for the treatment of pulmonary arterial hypertension” [abstract]. According to Gessler an “intriguing novel strategy for further improvements of inhaled treprostinil is the development of treprostinil-containing controlled release formulations such as liposomes or nanoparticles designed for aerosol delivery. Such formulations
will not only help to reduce the frequency of daily inhalations but also to facilitate sustained release of the vasoactive drug locally in the diseased lung without treatment gap during night time” [p. 203, para. 2].
Gessler does not disclose a phospholipid, a pH gradient salt, and a treprostinil to phospholipid weight ratio.
Pilkiewicz discloses an “inhalation system of a composition having lipids and a bioactive agent” wherein the composition can include liposomes [p. 4, line 7] and the bioactive agent includes antihypertensive agents [p. 4, line 25]. The compositions are usually in the form of suspensions (i.e., liposomes suspended in an external medium; limitation of instant claim 25) [p. 14, lines 13-14]. Specifically, the lipid comprise a phosphatidylcholine, a negatively charged lipid, and a sterol in the molar ratio of 1-20:1-10:0.5-5 (e.g., 7:1:2 mole ratio; 70 mole % phospholipid, 20 mole % sterol, 10 mole % negatively charged lipid, respectively; instant claim 34) [p. 2, lines 24-25]. Wherein suitable phospholipids include hydrogenated soya phosphatidylcholine (HSCP; i.e., a phosphatidylcholine and limitations of instant claims 32, 33, 35-39) [p. 5, line 16], suitable negatively charged lipid include distearoylphosphatidylglycerol (DSPG; instant claims 32, 33, 35-38) [p. 6, lines 18-20] and suitable sterols include cholesterol (i.e., instant claims 29-31, 35) [p. 5, line 31]. Pilkiewicz desires a transmembrane ion gradient: “Aside from inducing greater uptake, such transmembrane gradients also act to increase drug retention in the liposomes” [p. 12, lines 28-29] and teaches sustained release [p. 6, lines 23-29]. Pilkiewicz also teaches the use of pH gradient for drug loading [p. 13, lines 18-20]. Pilkiewicz discloses the “bioactive agent: lipid mixture weight ratio can vary from 10 : 1 to 1 : 500” [p. 8, line 1].
Gessler and Pilkiewicz do not discloses a method for loading Treprostinil into the liposomes.
Hariharan discloses that treprostinil is a weakly acidic drug [p. 24, line 3].
Clerc discloses a “method of stably encapsulating a weak acid drug in
liposomes, at a high concentration” [abstract] which involves a “salt of a weak acid to generate a higher inside/lower outside pH gradient” (i.e., pH gradient salt and pH of internal phase is higher; instant claims 25(b)(2), 41 and 45) [abstract]. The “vesicle-forming lipid is its ability to either (a) form spontaneously into bilayer vesicles in water, as exemplified by the phospholipids” [col. 5, lines 48-50]. Clerc discloses that “[t]ypically, weak acid compounds [active agents] to be loaded are added to the bulk medium at concentrations ranging from 1 uM-100 mM, with the concentration selected depending upon both the absolute quantity of drug intended for encapsulation and the degree of loading efficiency desired” (i.e., quantity of drug intended for encapsulation is adjustable) [col. 11, lines 16-20].
Gessler, Pilkiewicz, Hariharan and Clerc do not disclose a treprostinil to phospholipid weight ratio.
Chountoulesi discloses that “the drug-to-lipid ratio (D/L ratio), which is a critical process parameter, expresses the actual capacity of the liposome to accommodate the drug and can play a key role at the optimization of every liposomal formulation […] Furthermore, D/L ratio influences the therapeutic efficacy of the liposomal product, expressing the actual dose of the drug being administrated” [abstract]. In the first two paragraphs of column 2 of page 250, Chountoulesi explains:
“When initial D/L ratio is too high (>0.95), the loading efficiency is low, probably due to excess of drug that exceeds the liposomal loading capacity. In some cases, such overloading damages the liposomal membrane, leading to drug release and therefore lower final D/L ratio. When the D/L ratio is lower (</=0.95), it is possible to achieve better ‘‘loading efficiency”. Therefore, it is crucial to know the D/L ratio, which is required to achieve high loading efficiency, before starting the loading process.
“It is obvious that during the preformulation studies, all physicochemical parameters affecting the liposomal formulation should be evaluated. The degree of drug loading depends on the nature (i.e. physicochemical properties) of drugs and the composition of the liposomes (lipids, lipid/cholesterol ratio, drug/lipid ratio and charge of the liposomes), as well as the method used for preparation” (internal citations omitted).
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the treprostinil of Gessler with the liposomal compositions of Pilkiewicz. One would have been motivated to make this combination because Pilkiewicz discloses an inhalable liposomal formulation with sustained release for antihypertensive active agents, as expressly desired by Gessler. One would have had an expectation of success because Pilkiewicz teaches antihypertension agents in an inhalable liposomal composition.
It also would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the methods of loading a weak acid active agent into a liposome disclosed by Clerc with the liposomal Treprostinil composition taught by Gessler and Pilkiewicz. One would have been motivated to make this combination because Pilkiewicz desires a transmembrane ion gradient. One would have had an expectation of success because Hariharan discloses Treprostinil is a weakly acidic active agent, as required by Clerc.
Finally, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have narrowed active agent to lipid weight ratio disclosed by Pilkiewicz to the drug to lipid ratio disclosed by Chountoulesi. One would have been motivated to do so because Chountoulesi discloses that a drug to lipid ratios at or below 0.95 improves the loading efficiency of the liposomes. One would have had an expectation of success because the ratio range taught by Chountoulesi is within the acceptable ratio range taught by Pilkiewicz, and Clerc teaches the quantity of drug intended for encapsulation is adjustable.
Additionally, in combining the elements discussed in the above three paragraphs one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07. In the present case it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected HSPC, DSPG and cholesterol as the phospholipid, negatively charged lipid and sterol desired by Pilkiewicz because Pilkiewicz discloses each are suitable phospholipids, negatively charged lipids and sterols.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the present case, the instantly claimed ranges for Treprostinil to the at least one vesicle forming phospholipid (i.e., 0.035 or higher, 0.042 or higher, 0.052 or higher and 0.056 or higher; instant claims 25-28) overlap with the range taught by the prior art (0.95 or less) and so a prima facie case of obviousness exists. Furthermore, the instantly claimed ranges of 50-70 mole % of the first phospholipid, 20-45 mole % of a sterol, and 0.1-10 mole % of the second phospholipid (instant claim 34) overlap with the ranges taught by the prior art of, for example, 70 mole % phospholipid (i.e., HSPC; first phospholipid), 10 mole % negatively charged lipid (i.e., DSPG; second phospholipid), 20 mole % sterol (i.e., cholesterol) and so a prima facie case of obviousness exists.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated a composition for inhalation (instant claim 47) comprising a plurality of liposomes suspended in an external medium, wherein the liposomes comprise at least one vesicle-forming phospholipid and an encapsulated internal aqueous medium comprising treprostinil, and a pH gradient salt. Wherein a weight ratio of treprostinil to the at least one vesicle-forming phospholipid is within the instantly claimed ranges (i.e., instant claims 25-28). Wherein the liposome (lipid bilayer) comprises a cholesterol (instant claims 29-31), a first phospholipid of hydrogenated soy phosphatidylcholine (instant claims 32, 33, and 35-39) and a second phospholipid of a negatively charged distearoylphosphatidylglycerol (instant claims 32, 33, 35-38). Wherein the liposome comprise the first phospholipid, sterol and second phospholipid within the instantly claimed mole percents (instant claim 34). Wherein the pH gradient salt comprises a weak acid salt (instant claim 41) and the internal pH of the liposome is higher than the external pH (instant claim 45).
Regarding instant claim 40, Pilkiewicz discloses the lipid makeup may also be phosphatidylcholines: positively-charged lipids: sterol compounds [p. 3, lines 7-8] wherein suitable phospholipids include hydrogenated soya phosphatidylcholine (HSCP) [p. 5, line 16] and suitable positively charged lipids include 1,2-bis(oleoyloxy)-3-(trimethylammonio )propane (DOTAP) [p. 6, line 16].
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07. In the present case it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected HSPC and DOTAP as the phospholipid and positively charged lipid in the liposomal composition discussed above because Pilkiewicz discloses they are suitable phospholipids and positively charged lipids for the desired liposome.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated the inhalable compositions taught by Gessler, Pilkiewicz, Hariharan, Clerc and Chountoulesi, as discussed above, wherein the liposome comprises HSPC and DOTAP.
Regarding instant claim 43, Clerc discloses “Exemplary weak acids for use in the invention include carboxylic acids” [col. 3, lines 17-18].
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07. In the present case it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected a carboxylic acid salt as the weak acid salt desired by Clerc because Clerc discloses carboxylic acids are suitable weak acids for that purpose.
2) Claims 46 and 48-53 are rejected under 35 U.S.C. 103 as being unpatentable over Gessler et al. (Therapeutic Advances in Respiratory Disease, 2011, v. 5, no. 3, p. 195-206) in view of Pilkiewicz et al. (WO 2000/27359, publication date 05/18/2000), Hariharan et a. (Clinical Pharmacology and Biopharmaceutics Reviews; 203496Orig1s000, 2011), Clerc et al. (US 5,939,096, date of patent 08/17/1999), and Chountoulesi et al. (Journal of Liposome Research, 2018 (published online 06/06/2017), v. 28, no. 3, p. 249-258) as applied to claims 25-41, 43, 45, and 47 above, and further in view of Malinin et al. (WO 2015/138423 A1, publication date 09/17/2015).
Gessler, Pilkiewicz, Hariharan, Clerc, and Chountoulesi, which are taught above, differ from the instant claims insofar as they do not teach the instantly claimed particle size, polydispersity and release characteristics.
Regarding instant claim 46, Clerc discloses that “The liposomes are preferably uniformly sized to a selected size range between 0.04 to 0.25um” (uniform, i.e., low polydispersity index) [col. 7, lines 36-38].
Malinin relates to liposomal Treprostinil compositions for inhalation [abstract] and discloses that the mean particle diameter may be about 200 nm or less [p. 67, claim 9].
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the present case, the instantly claimed range of 100-200nm overlaps with the prior art range of less than 200nm and so a prima facie case of obviousness exists.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" (see MPEP 2144.05 IIA quoting In re Aller, 220 F.2d 454, 456 (105 USPQ 233)). In the present, case a skilled artisan would have been motivated to optimize to the polydispersity of the prior art to achieve the desirable effect of a uniform distribution, as desired by Clerc. A skilled artisan would have had an expectation of success because Clerc disclosed “uniformly sized” liposomes.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated the liposomal treprostinil composition taught by Gessler, Pilkiewicz, Hariharan, Clerc, and Chountoulesi, as discussed above, wherein the liposomes have an average particle size and polydispersity index as instantly claimed.
Regarding instant claims 48-53, Pilkiewicz teaches that phosphatidylcholines, the negatively charged lipids and sterols all affect the release characteristics of the formulation [p. 6, lines 23-30].
Malinin discloses “[t]he current inhaled prostanoid products are iloprost (Ventavisc.rs\ 6-9 inhalation treatments per day) and treprostinil (Tyvaso(jy, 4 inhalation treatments per day, spaced 4 hours apart). While longer than that for iloprost, the half-life of treprostinil is still relatively short necessitating dosing every 4 hours over the time patients are awake” [0005]. In contrast, Malinin desires a once-a-day formulations of Treprostinil with a sustained release in the lungs over a time period ranging from 12 hours to 24 hours [0023 & 0124].
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated the liposomal Treprostinil composition taught be Gessler, Pilkiewicz, Hariharan, Clerc, and Chountoulesi, as discussed above, to have a release kinetics within the instantly claimed parameters through routine optimization. It has been held that it is not inventive to discover the optimum workable ranges by routine experimentation where, as is here, the general conditions of the claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Given the relatively short half-life of Treprostinil, and to avoid to disadvantages of the prior art formulations identified by Malinin, a skilled artisan would have been motivated to optimize the release characteristics of the composition taught above to deliver a steady amount of Treprostinil over a 24 hour period. That is to say, a skilled artisan would have been motivated to lower the initial release (i.e., within 2 hours) and maximize the complete release of Treprostinil within 24 hours. One would have had an expectation of success because Pilkiewicz teaches the sustained release is affected by the makeup of the liposome.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated the Treprostinil composition taught be Gessler, Pilkiewicz, Hariharan, Clerc, and Chountoulesi, as discussed above, to have release characteristics within the instantly claimed parameters (i.e., less than 60%, 50% and 40% released within 2 hours; more than 80% released within 72, 48 and 25 hours).
3) Claims 25 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Gessler et al. (Therapeutic Advances in Respiratory Disease, 2011, v. 5, no. 3, p. 195-206) in view of Pilkiewicz et al. (WO 2000/27359, publication date 05/18/2000), Woodle et al. (WO 1996/25147, publication date 08/22/1996), Roscigno et al. (WO2017192993 A1, publication date 11/09/2017), and Chountoulesi et al. (Journal of Liposome Research, 2018 (published online 06/06/2017), v. 28, no. 3, p. 249-258).
Gessler discloses that “[i]nhaled treprostinil is a safe and well-tolerated approved pharmaceutical for the treatment of pulmonary arterial hypertension” [abstract]. According to Gessler an “intriguing novel strategy for further improvements of inhaled treprostinil is the development of treprostinil-containing controlled release formulations such as liposomes or nanoparticles designed for aerosol delivery. Such formulations
will not only help to reduce the frequency of daily inhalations but also to facilitate sustained release of the vasoactive drug locally in the diseased lung without treatment gap during night time” [p. 203, para. 2].
Gessler does not disclose a phospholipid, a pH gradient salt, and a treprostinil to phospholipid weight ratio.
Pilkiewicz discloses an “inhalation system of a composition having lipids and a bioactive agent” wherein the composition can include liposomes [p. 4, line 7] and the bioactive agent includes antihypertensive agents [p. 4, line 25]. The compositions are usually in the form of suspensions (i.e., liposomes suspended in an external medium; limitation of instant claim 25) [p. 14, lines 13-14]. Specifically, the lipid comprise a phosphatidylcholine (i.e., at least one phospholipid) [p. 2, lines 24-25]. Pilkiewicz desires a transmembrane ion gradient: “Aside from inducing greater uptake, such transmembrane gradients also act to increase drug retention in the liposomes” [p. 12, lines 28-29] and teaches sustained release [p. 6, lines 23-29]. Pilkiewicz also teaches the use of pH gradient for drug loading [p. 13, lines 18-20]. Pilkiewicz discloses the “bioactive agent: lipid mixture weight ratio can vary from 10 : 1 to 1 : 500” [p. 8, line 1].
Gessler and Pilkiewicz do not disclose a method of loading the Treprostinil into the liposomes.
Woodle discloses liposome compositions having an inside/outside pH gradient and comprising active compounds having a reactive hydroxyl group [abstract]. According to Woodle, one loading method is by reverse pH gradient wherein the internal liposome pH is higher than the pH of the external medium [paragraph spanning pages 22-23]. “Preferably, the pH of the internal phase of the liposomes is substantially greater than the pKa of the free carboxylic acid group [on the active agent], and preferably by at least 1-2 units above this pKa value” [p. 23, lines 5-7]. In one embodiment, “the liposomes are prepared in the presence of a bicarbonate salt, e.g., 200 mM sodium bicarbonate at a selected pH, e.g., 5-9” [p. 23, lines 8-9].
Roscigno discloses the pKa of treprostinil is 4.5 [0053].
Chountoulesi discloses that “the drug-to-lipid ratio (D/L ratio), which is a critical process parameter, expresses the actual capacity of the liposome to accommodate the drug and can play a key role at the optimization of every liposomal formulation […] Furthermore, D/L ratio influences the therapeutic efficacy of the liposomal product, expressing the actual dose of the drug being administrated” [abstract]. In the first two paragraphs of column 2 of page 250, Chountoulesi explains:
“When initial D/L ratio is too high (>0.95), the loading efficiency is low, probably due to excess of drug that exceeds the liposomal loading capacity. In some cases, such overloading damages the liposomal membrane, leading to drug release and therefore lower final D/L ratio. When the D/L ratio is lower (</=0.95), it is possible to achieve better ‘‘loading efficiency”. Therefore, it is crucial to know the D/L ratio, which is required to achieve high loading efficiency, before starting the loading process.
“It is obvious that during the preformulation studies, all physicochemical parameters affecting the liposomal formulation should be evaluated. The degree of drug loading depends on the nature (i.e. physicochemical properties) of drugs and the composition of the liposomes (lipids, lipid/cholesterol ratio, drug/lipid ratio and charge of the liposomes), as well as the method used for preparation” (internal citations omitted).
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the treprostinil of Gessler with the liposomal compositions of Pilkiewicz. One would have been motivated to make this combination because Pilkiewicz discloses an inhalable liposomal formulation with sustained release for antihypertensive active agents, as expressly desired by Gessler. One would have had an expectation of success because Pilkiewicz teaches antihypertension agents in an inhalable liposomal composition.
It also would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the loading methods of Woodle with the liposomal Treprostinil composition taught by Gessler and Pilkiewicz. One would have been motivated to make this combination because Pilkiewicz desires a transmembrane ion gradient. One would have had an expectation of success because Woodle discloses a pH gradient suitable for loading drugs having a carboxylic group and according to Roscigno the pKa of Treprostinil would have made it suitable for the methods of Woodle (i.e., pKa of Treprostinil is 1-2 units less than the internal pH disclosed by Woodle).
Finally, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have narrowed weight ratio of active agent to lipid disclosed by Pilkiewicz to the drug to lipid ratio disclosed by Chountoulesi. One would have been motivated to do so because Chountoulesi discloses that drug to lipid ratios at or below 0.95 improve the loading efficiency of the liposomes. One would have had an expectation of success because the ratio range taught by Chountoulesi is within the acceptable ratio range taught by Pilkiewicz.
Additionally, in combining the elements discussed in the three paragraphs above one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the present case, the instantly claimed ranges for Treprostinil to the at least one vesicle forming phospholipid (i.e., 0.035 or higher, 0.042 or higher, 0.052 or higher and 0.056 or higher; instant claims 25) overlap with the range taught by the prior art (0.95 or less) and so a prima facie case of obviousness exists.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated a composition for inhalation comprising a plurality of liposomes suspended in an external medium, wherein the liposomes comprise at least one vesicle-forming phospholipid and an encapsulated internal aqueous medium comprising treprostinil, and a pH gradient salt. Wherein a weight ratio of treprostinil to the at least one vesicle-forming phospholipid is within the instantly claimed range. Wherein the pH gradient salt is a bicarbonate salt (i.e., instant claim 42).
4) Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Gessler et al. (Therapeutic Advances in Respiratory Disease, 2011, v. 5, no. 3, p. 195-206) in view of Pilkiewicz et al. (WO 2000/27359, publication date 05/18/2000), Woodle et al. (WO 1996/25147, publication date 08/22/1996), Roscigno et al. (WO2017192993 A1, publication date 11/09/2017), and Chountoulesi et al. (Journal of Liposome Research, 2018 (published online 06/06/2017), v. 28, no. 3, p. 249-258) as applied to claims 25 and 42 above, and further in view of Clerc et al. (US 5939096, date of patent 08/17/1999).
Gessler, Pilkiewicz, Woodle, Roscigno and Chountoulesi, which are taught above, differ from the instant claims insofar as they do not teach the instantly claimed pH gradient established by a polar amino acid. Woodle does discloses glutamate is suitable for creating a pH gradient with an internal pH of 5.5 (i.e., polar amino acid pH gradient salt) [p. 17, line 10].
Clerc discloses a “method of stably encapsulating a weak acid drug in
liposomes, at a high concentration” [abstract] which involves a “salt of a weak acid to generate a higher inside/lower outside pH gradient” (i.e., pH gradient salt and pH of internal phase is higher) [abstract]. “The hydration medium is preferably at least 50 mM weak acid salt, and typically between 50-300 mM. The medium is adjusted, e.g., by addition of acid, to a pH of between 5 and 7” [col. 7, lines 24-27].
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have established the pH gradient desired by Woodle using with glutamate buffer of Woodle. One would have been motivated to use the glutamate buffer because Clerc discloses weak acid salts are suitable for loading weakly acidic drugs into liposomes. One would have had an expectation of success because Woodle discloses the glutamate buffer is able to form an internal pH that is at least 1 unite higher than the pKa of Treprostinil, as desired by Woodle. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated the liposomal treprostinil composition taught by Gessler, Pilkiewicz, Woodle, Roscigno, and Chountoulesi, as discussed above, wherein the liposome comprises a salt of a polar amino acid (glutamate).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
1) Claims 25-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11229616B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the conflicting claims both claim a composition comprising one or more liposome suspended in an external medium, said liposome comprising (a) an external lipid bilayer, comprising at least one vesicle-forming phospholipid, (b) an internal aqueous medium, comprising treprostinil and a salt to provide a pH gradient, wherein the weight ratio of treprostinil to the at least one vesicle-forming phospholipid is equal to or higher than about 0.056 [instant claims 25-28; claims 1-4]. Wherein the liposome may further comprise cholesterol [instant claims 29-31; claims 5-6]. Wherein the vesicle forming phospholipids include HSPC, DSPG and DOTAP [instant claims 32, 33, 35-40; claims 17-18]. The claims embrace the same pH gradient salts [instant claims 41-44; claims 7-10] and release characteristics [instant claims 48-53; claims 1, 13, 14].
2) Claims 25-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11964050B2 in view of Chountoulesi et al. (Journal of Liposome Research, 2018 (published online 06/06/2017), v. 28, no. 3, p. 249-258).
The instant claims and the conflicting claims both embrace a composition comprising liposomes of HSPC, DSPG and cholesterol which encapsulate pH gradient salt (bicarbonate and a weak acid) and Treprostinil [instant claims 1, 29-33, 25-39; claim 1].
The conflicting claims do not disclose the instantly claimed drug to lipid weight ratio.
Chountoulesi discloses that “the drug-to-lipid ratio (D/L ratio), which is a critical process parameter, expresses the actual capacity of the liposome to accommodate the drug and can play a key role at the optimization of every liposomal formulation […] Furthermore, D/L ratio influences the therapeutic efficacy of the liposomal product, expressing the actual dose of the drug being administrated” [abstract]. In the first two paragraphs of column 2 of page 250, Chountoulesi explains:
“When initial D/L ratio is too high (>0.95), the loading efficiency is low, probably due to excess of drug that exceeds the liposomal loading capacity. In some cases, such overloading damages the liposomal membrane, leading to drug release and therefore lower final D/L ratio. When the D/L ratio is lower (</=0.95), it is possible to achieve better ‘‘loading efficiency”. Therefore, it is crucial to know the D/L ratio, which is required to achieve high loading efficiency, before starting the loading process.
“It is obvious that during the preformulation studies, all physicochemical parameters affecting the liposomal formulation should be evaluated. The degree of drug loading depends on the nature (i.e. physicochemical properties) of drugs and the composition of the liposomes (lipids, lipid/cholesterol ratio, drug/lipid ratio and charge of the liposomes), as well as the method used for preparation” (internal citations omitted).
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the drug to lipid ratio of Chountoulesi with the composition of the conflicting claims because Chountoulesi discloses that with a ratio of 0.95 or less it is possible to achieve better loading efficiency. A skilled artisan would have had an expectation of success because adjusting the ratio simply depends on the amount of drug and the amount of lipids used. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
3) Claims 25-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12220483B2 in view of Chountoulesi et al. (Journal of Liposome Research, 2018 (published online 06/06/2017), v. 28, no. 3, p. 249-258).
The instant claims and the conflicting claims both embrace a composition comprising liposomes of HSPC, DSPG and cholesterol which encapsulate pH gradient salt (bicarbonate and a weak acid) and Treprostinil [instant claims 1, 29-33, 25-39; claims 1, 9 and 15].
The conflicting claims do not disclose the instantly claimed drug to lipid weight ratio.
Chountoulesi discloses that “the drug-to-lipid ratio (D/L ratio), which is a critical process parameter, expresses the actual capacity of the liposome to accommodate the drug and can play a key role at the optimization of every liposomal formulation […] Furthermore, D/L ratio influences the therapeutic efficacy of the liposomal product, expressing the actual dose of the drug being administrated” [abstract]. In the first two paragraphs of column 2 of page 250, Chountoulesi explains:
“When initial D/L ratio is too high (>0.95), the loading efficiency is low, probably due to excess of drug that exceeds the liposomal loading capacity. In some cases, such overloading damages the liposomal membrane, leading to drug release and therefore lower final D/L ratio. When the D/L ratio is lower (</=0.95), it is possible to achieve better ‘‘loading efficiency”. Therefore, it is crucial to know the D/L ratio, which is required to achieve high loading efficiency, before starting the loading process.
“It is obvious that during the preformulation studies, all physicochemical parameters affecting the liposomal formulation should be evaluated. The degree of drug loading depends on the nature (i.e. physicochemical properties) of drugs and the composition of the liposomes (lipids, lipid/cholesterol ratio, drug/lipid ratio and charge of the liposomes), as well as the method used for preparation” (internal citations omitted).
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the drug to lipid ratio of Chountoulesi with the composition of the conflicting claims because Chountoulesi discloses that with a ratio of 0.95 or less it is possible to achieve better loading efficiency. A skilled artisan would have had an expectation of success because adjusting the ratio simply depends on the amount of drug and the amount of lipids used. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
4) Claims 25-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12551437B2 in view of Chountoulesi et al. (Journal of Liposome Research, 2018 (published online 06/06/2017), v. 28, no. 3, p. 249-258).
The instant claims and the conflicting claims both embrace a composition comprising liposomes of HSPC, DSPG and cholesterol which encapsulate pH gradient salt (bicarbonate) and Treprostinil [instant claims 1, 29-33, 25-39; claims 1, 6 and 15].
The conflicting claims do not disclose the instantly claimed drug to lipid weight ratio.
Chountoulesi discloses that “the drug-to-lipid ratio (D/L ratio), which is a critical process parameter, expresses the actual capacity of the liposome to accommodate the drug and can play a key role at the optimization of every liposomal formulation […] Furthermore, D/L ratio influences the therapeutic efficacy of the liposomal product, expressing the actual dose of the drug being administrated” [abstract]. In the first two paragraphs of column 2 of page 250, Chountoulesi explains:
“When initial D/L ratio is too high (>0.95), the loading efficiency is low, probably due to excess of drug that exceeds the liposomal loading capacity. In some cases, such overloading damages the liposomal membrane, leading to drug release and therefore lower final D/L ratio. When the D/L ratio is lower (</=0.95), it is possible to achieve better ‘‘loading efficiency”. Therefore, it is crucial to know the D/L ratio, which is required to achieve high loading efficiency, before starting the loading process.
“It is obvious that during the preformulation studies, all physicochemical parameters affecting the liposomal formulation should be evaluated. The degree of drug loading depends on the nature (i.e. physicochemical properties) of drugs and the composition of the liposomes (lipids, lipid/cholesterol ratio, drug/lipid ratio and charge of the liposomes), as well as the method used for preparation” (internal citations omitted).
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the drug to lipid ratio of Chountoulesi with the composition of the conflicting claims because Chountoulesi discloses that with a ratio of 0.95 or less it is possible to achieve better loading efficiency. A skilled artisan would have had an expectation of success because adjusting the ratio simply depends on the amount of drug and the amount of lipids used. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
5) Claims 25-53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 19/454,159 (US 2026/0144751 A1) in view of Chountoulesi et al. (Journal of Liposome Research, 2018 (published online 06/06/2017), v. 28, no. 3, p. 249-258).
The instant claims and the copending claims both embrace a composition comprising liposomes of HSPC, DSPG and cholesterol which encapsulate pH gradient salt (bicarbonate) and Treprostinil [instant claims 1, 29-33, 25-39; claims 1, 6 and 15].
The conflicting claims do not disclose the instantly claimed drug to lipid weight ratio.
Chountoulesi discloses that “the drug-to-lipid ratio (D/L ratio), which is a critical process parameter, expresses the actual capacity of the liposome to accommodate the drug and can play a key role at the optimization of every liposomal formulation […] Furthermore, D/L ratio influences the therapeutic efficacy of the liposomal product, expressing the actual dose of the drug being administrated” [abstract]. In the first two paragraphs of column 2 of page 250, Chountoulesi explains:
“When initial D/L ratio is too high (>0.95), the loading efficiency is low, probably due to excess of drug that exceeds the liposomal loading capacity. In some cases, such overloading damages the liposomal membrane, leading to drug release and therefore lower final D/L ratio. When the D/L ratio is lower (</=0.95), it is possible to achieve better ‘‘loading efficiency”. Therefore, it is crucial to know the D/L ratio, which is required to achieve high loading efficiency, before starting the loading process.
“It is obvious that during the preformulation studies, all physicochemical parameters affecting the liposomal formulation should be evaluated. The degree of drug loading depends on the nature (i.e. physicochemical properties) of drugs and the composition of the liposomes (lipids, lipid/cholesterol ratio, drug/lipid ratio and charge of the liposomes), as well as the method used for preparation” (internal citations omitted).
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the drug to lipid ratio of Chountoulesi with the composition of the copending claims because Chountoulesi discloses that with a ratio of 0.95 or less it is possible to achieve better loading efficiency. A skilled artisan would have had an expectation of success because adjusting the ratio simply depends on the amount of drug and the amount of lipids used. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
This is a provisional nonstatutory double patenting rejection.
6) Claims 25-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 12064406B2 in view of Chountoulesi et al. (Journal of Liposome Research, 2018 (published online 06/06/2017), v. 28, no. 3, p. 249-258).
The instant claims and the conflicting claims both embrace a composition comprising liposomes of HSPC, DSPG and cholesterol which encapsulate pH gradient salt (bicarbonate salt) and Treprostinil [instant claims 1, 29-33, 25-39; claims 1].
The conflicting claims do not disclose the instantly claimed drug to lipid weight ratio.
Chountoulesi discloses that “the drug-to-lipid ratio (D/L ratio), which is a critical process parameter, expresses the actual capacity of the liposome to accommodate the drug and can play a key role at the optimization of every liposomal formulation […] Furthermore, D/L ratio influences the therapeutic efficacy of the liposomal product, expressing the actual dose of the drug being administrated” [abstract]. In the first two paragraphs of column 2 of page 250, Chountoulesi explains:
“When initial D/L ratio is too high (>0.95), the loading efficiency is low, probably due to excess of drug that exceeds the liposomal loading capacity. In some cases, such overloading damages the liposomal membrane, leading to drug release and therefore lower final D/L ratio. When the D/L ratio is lower (</=0.95), it is possible to achieve better ‘‘loading efficiency”. Therefore, it is crucial to know the D/L ratio, which is required to achieve high loading efficiency, before starting the loading process.
“It is obvious that during the preformulation studies, all physicochemical parameters affecting the liposomal formulation should be evaluated. The degree of drug loading depends on the nature (i.e. physicochemical properties) of drugs and the composition of the liposomes (lipids, lipid/cholesterol ratio, drug/lipid ratio and charge of the liposomes), as well as the method used for preparation” (internal citations omitted).
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the drug to lipid ratio of Chountoulesi with the composition of the conflicting claims because Chountoulesi discloses that with a ratio of 0.95 or less it is possible to achieve better loading efficiency. A skilled artisan would have had an expectation of success because adjusting the ratio simply depends on the amount of drug and the amount of lipids used. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
Conclusion
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/C.T.W./ Examiner, Art Unit 1612
/SAHANA S KAUP/ Supervisory Primary Examiner, Art Unit 1612
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