-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 .
Applicant's response dated August 28, 2026 is acknowledged.
Priority
This application is a continuation of 15/930,532 filed on 05/13/2020, which claims
benefit in provisional application 62/847,337 filed on 05/14/2019.
Claim Status
Claims 1-21 are pending. Claims 13-20 remain withdrawn. Claims 1-4, 9, and 12 were amended. Claim 21 was newly added and reads on the elected invention. Claims 1-12 and 21 are examined.
Withdrawn Claim Objections
Objections to claims 3 and 4 are withdrawn because objections were obviated with claim amendments.
Withdrawn Claim Rejections - 35 USC § 112
Rejections of claims 1-12 are withdrawn because rejections were obviated with claim amendments.
New Claim Objections
Claim 3 is objected because the “l” in the chemical name “distearoyl l phosphatidylglycerol” appears to be a typographical error. Appropriate correction is required.
Maintained and New Claim Rejections - 35 USC § 103
Necessitated by Amendment
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.
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.
Claims 1-3, 6, 8-12, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over
Lenk (US 5,262,168 Date of Patent November 16, 1993 - of record in IDS dated 07/22/2024)
and Nicolls (US 2013/0251787 Al Published September 26, 2013 - of record in IDS dated
07/22/2024).
The claims encompass a pharmaceutical composition.
The teachings of Lenk are related to a liposome composition comprising a prostaglandin,
a lipid, and a drying protectant. The liposomes may be loaded with prostaglandin passively, or
using a transmembrane concentration gradient, preferably using a transmembrane pH gradient.
Using this transmembrane loading technique, trapping efficiencies of 50% to 100% are achieved,
and the release rate of the prostaglandin from the liposomes is reduced. The liposome size is
maintained after lyophilization and reconstitution (Abstract). The liposomes are formed initially
in an aqueous solution of relatively basic pH, and the pH is later adjusted to a relatively acidic
pH. Upon acidification of the liposomal external solution the prostaglandin becomes associated
with the liposomes. Such association may be by partitioning into and through the liposomal
membranes. Such a procedure surprisingly results in a 50 to 100% entrapment of the
prostaglandin in the liposomes. The buffering system used to achieve this entrapment, is
therefore called a partition-enhancing buffer. The resulting liposomes are size-reduced to a
homogenous size distribution. Following pH adjustment, the resulting solution can be dehydrated
or lyophilized and stored until use, then it may be rehydrated using an aqueous solution (column
3 lines 35-49). The liposomes may be prepared by associating the prostaglandin with the lipid by
means of a transmembrane pH gradient. This gradient may be obtained by first forming the
liposomes in a basic aqueous medium, adding the prostaglandin to the aqueous suspension, and
then acidifying the external (aqueous) medium of the liposomes. The basic external medium may
be a saccharide solution, while the acidification may be achieved by use of an acidic solution
such as a citric acid solution (column 4 lines 49-58). The term lipid means any suitable material
resulting in a bilayer upon admixture with an aqueous medium such that the hydrophobic portion
of the lipid material orients toward the bilayer while a hydrophilic portion orients toward the
aqueous phase. Lipids include cholesterol and amphipathic lipids. Lipids include
phosphatidylcholine and phosphatidylethanolamine, among others, and combinations thereof.
The liposome can contain other steroid components including combinations of cholesterol and
EPC (column 9 lines 32-52). In the case of loading the liposomes via a pH gradient wherein the
first external medium is basic, suitable aqueous media include buffers adjusted to pH 3.0 to
about 11.0. In cases where the first buffer used is basic, buffers such as phosphate buffer may be
used a pH 7-9. Alternatively, a sodium carbonate or bicarbonate buffer may be used (column 9
lines 53-63).
Lenk does not teach treprostinil or iloprost.
The teachings of Nicolls are related to compositions for treating pulmonary arterial
hypertension comprising administering an effective dose of leukotriene inhibitor (Abstract). In
one embodiment, a treatment method includes administering a combination therapy including an
additional active agent such as a prostaglandin selected from treprostinil and iloprost (paragraphs
0014 and 00193). In some embodiments, the composition is in the form of liposomes (paragraph
0209). Suitable liposomes for use in the present formulations are known in the art. For example,
suitable liposomes include cholesterol, 1 ,2-distearoyl-snglycero-3-phosphocholine (DSPC) and
PEG-DSPE, with the weight ratio being about 5:10:1. In some embodiments, the liposome
formulation comprises about 0.1-25%, e.g., 0.1 %, 1 %, 5%, 10% or 20% (w/w) of a
phospholipid, such as dipalmitoylphosphatidylcholine (DPPC) and 1,2-distearoylsn-glycero-3-
phosphocholine (DSPC) (paragraph 0210).
The teachings Lenk and Nicolls are related to liposome compositions comprising
prostaglandins and it would have been obvious to have combined their teachings because they
are in the same field of endeavor.
Regarding claim 1, it would have been prima facie obvious to a person of ordinary skill
in the art before the effective filing date of the claimed invention to have formed a
pharmaceutical composition comprising one or more liposomes suspended in an external
medium, said liposomes formed from an external lipid bilayer and an internal aqueous medium
wherein the internal aqueous medium comprises a bicarbonate salt and a prostaglandin, with a
reasonable expectation of success because Lenk teaches a pharmaceutical composition
comprising liposomes having an encapsulated aqueous medium comprising a prostaglandin.
Lenk teaches forming the liposomes by pH gradient where the liposomes are formed initially in
an aqueous solution of relatively basic pH, and the pH is later adjusted to a relatively acidic pH.
Upon acidification of the liposomal external solution, the prostaglandin becomes associated with
the liposomes.
It would have been obvious to have formed the basic medium with sodium
bicarbonate because Lenk teaches that sodium bicarbonate buffer is suitable form making the
basic aqueous medium.
It would have been obvious to have formed the liposomes with a lipid comprising a combination of cholesterol, phosphatidylcholine, and phosphatidylethanolamine, with a reasonable expectation of success because Lenk teaches forming the liposomes from a
lipid, where the term lipid means any suitable material resulting in a bilayer upon admixture with
an aqueous medium such that the hydrophobic portion of the lipid material orients toward the
bilayer while a hydrophilic portion orients toward the aqueous phase. Lipids include cholesterol
and amphipathic lipids. Lipids include phosphatidylcholine and phosphatidylethanolamine,
among others, and combinations thereof. Lenk teaches that liposomes are in a suspension upon
formation of liposomes (paragraph bridging columns 10-11, Examples 1, 2, 7, 8).
It would have been obvious to have selected treprostinil or iloprost as the prostaglandin
with a reasonable expectation of success because it was known from Nicolls that treprostinil and
iloprost are examples of prostaglandins known to be useful in forming liposome compositions.
The selection of a known material based on its suitability for its intended purpose supports
obviousness.
The last "wherein" clause in the claim describes properties of the composition. The prior
art composition contains the same components as claimed and meets all of the structural
limitations of the instantly claimed composition, and it would have been reasonable to expect the
prior art composition to have the same properties as claimed composition when placed under
identical test conditions.
It would have been obvious to have formed the liposome with sodium bicarbonate in a concentration sufficient to produce an internal aqueous medium having a pH in the range of 7-9, with a reasonable expectation of success because Lenk teaches using a buff er such as sodium bicarbonate to form an encapsulated aqueous medium having a pH in the range of 7-9. It would have been obvious to have acidified the external solution to a pH of 2.5-4.5 in order for form a pH gradient, with a reasonable expectation of success because Lenk teaches that regardless of the liposome forming procedure used to form the transmembrane pH gradient, an external medium comprising an aqueous solution of a second pH (a second external medium) having a relatively acidic pH with respect to the first external medium is added to the liposome solution. The pH of this second aqueous solution is generally about 2.5 to about 4.5. Upon adjustment of the first external medium by, for example, addition of this second aqueous solution, the pH of the liposome solution is about 3.0 to about 4.5 (paragraph bridging columns 7-8).
The claimed pH range 7-10 of the internal medium is obvious because it encompasses the prior art range of 7-9. The claimed pH ranges of the external medium of greater than the pKa of the acidic drug to less than 7 in claim 1 and greater than the pKa of the acidic drug to less than 6 in claim 9 overlap with the prior art pH range of 2.5-4.5.
Regarding claim 2, Lenk teaches using a combination of lipids to form the liposome
where the combination includes phosphatidyl choline and phosphatidylethanolamine (column 9
lines 32-52). Phosphatidylethanolamine reads on a positively or negatively charged
phospholipid.
Regarding claim 3, it would have been obvious to have formed the liposome from a
combination of cholesterol, DSPC, and PEG-DSPE, with a reasonable expectation of success
because the combination of cholesterol, DSPC, and PEG-DSPE was known from Nicolls as
suitable for making liposomes. The selection of a known material based on its suitability for its
intended purpose supports obviousness.
Regarding claim 6, Lenk modified by Nicolls teaches forming liposomes with
cholesterol.
The limitation of claim 8 is obvious because a concentration of sodium bicarbonate
present in the internal aqueous environment that is sufficient to produce a pH range of 7 -9 would have been at least close enough the claimed concentration of 50-600 mM that a person skilled in the art would have expected them to have the same properties. The specification was reviewed and there is no evidence that the claimed concentration range is critical.
Claims 10-12 and 21 describe composition properties. The prior art composition meets all of the structural limitations of the instantly claimed composition and it would have been reasonable to expect the prior art composition to have the same properties as claimed composition when tested under the same conditions. The prior art teaches the same drugs as claimed and the potency of said drugs would have been the same as claimed relative to the free drug.
Combining prior art elements according to known methods to obtain predictable results
supports obviousness.
Claims 4, 5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Lenk and
Nicolls as applied to claims 1-3, 6, 8-12, and 21 above, and further in view of Yang (US
2013/0115273 Al Published May 9, 2013).
The teachings of Lenk and Nicolls are relied upon as summarized above. They do not
teach the limitations of claims 4, 5, and 7.
The teachings of Yang are related to therapeutic liposomal compositions (Abstract). The
liposomes can contain any suitable lipid including cholesterol, phospholipids, and cationic lipids
(paragraph 0047). Suitable phospholipids include but are not limited to phosphatidylcholine
(PC), distearoyl phosphatidyl choline (DSPC), distearoyl phosphatidyl glycerol (DSPG),
hydrogenated soy phosphatidylcholine (HSPC), and DSPE-PEG2000 (paragraph 0048). Cationic
lipids contain positively charged functional groups under physiological conditions. Cationic
lipids include N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N(
1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), and 3-beta-[N(
N',N'-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol) (paragraph 0050). In some
embodiments, the therapeutic liposome includes one or more lipids which can be a phospholipid,
a steroid, and/or a cationic lipid (paragraph 0051). In some embodiments, the therapeutic
liposome comprises 40-80 mole% DSPC, 5-50 mole% cholesterol, 0-30 mole% DSPG, and
0-10 mole% DSPE-PEG(2000) (paragraph 0053). Therapeutic agents include prostaglandin J2
(paragraph 0058).
The teachings of Yang and Lenk modified by Nicolls are related to liposome
compositions comprising encapsulated prostaglandin, and it would have been obvious to have
combined them because they are in the same field of endeavor.
Regarding claims 4 and 5, it would have been obvious to have modified the liposomes in
Lenk as modified by Nicolls by forming the liposomes with lipids comprising HSPC, DSPC,
DSPG, DSPE-PEG200, DOTMA, DOTAP, DC-cholesterol, cholesterol, or any combination
thereof, with a reasonable expectation of success because said lipids were known from Yang as
useful for making liposomes intended for encapsulating active agents such as prostaglandins.
The selection of a known material based on its suitability for its intended purpose supports
obviousness.
Regarding claim 7, it would have been obvious to have formed Lenk's liposome as
modified by Nicolls with a mixture of 40-80 mole % DSPC, 5-50 mole % cholesterol, 0-30 mole
% DSPG, and 0-10 mole% DSPE-PEG(2000), with a reasonable expectation of success because
said combination of components was known from Yang as suitable for making liposomes
intended for encapsulating a prostaglandin. The selection of a known material based on its
suitability for its intended purpose supports obviousness. The claimed concentration range of the
first lipid is obvious over DSPC in a concentration of 40-80 mole% because the ranges overlap.
The claimed concentration of cholesterol is obvious because it overlaps with 5-50 mole %
concentration of cholesterol in Yang. The claimed concentration of second phospholipid is
obvious because it overlaps with the combined concentration of 0-30 mole% DSPG and 0-10
mole % DSPE-PEG(2000).
Maintained and New Double Patenting Rejections
Necessitated by Amendment
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.
Claim 1-12 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,833,125 B2 in view of Lenk, Nicolls, Yang, individually or in a combination.
Patented claims are drawn to a treatment method that requires a pharmaceutical
composition comprising one or more liposomes comprising an external lipid bilayer comprising
at least one vesicle-forming phospholipid, and an internal aqueous medium comprising
Treprostinil and a salt to provide a pH gradient between the internal aqueous medium. The
external lipid bilayer further comprising a sterol selected from cholesterol, cholesterol
hexasuccinate, ergosterol, lanosterol, or any combination thereof. The salt to provide a pH
gradient is a bicarbonate salt. The vesicle-forming lipid is a mixture of a first phospholipid and a
second phospholipid or a mixture of a first phospholipid and a charged lipid. The first
phospholipid is phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI),
phosphatidic acid (PA), phosphatidyethanolamine (PE), phosphatidylserine (PS) or any
combination thereof, the second phospholipid is a PEG modified phospholipid, a positively
charged or a negatively charged phospholipid, and the charged lipid is a positively charged or a
negatively charged lipid. The first phospholipid is HSPC, DSPC, DPPC, DMPC or any
combination thereof and the second phospholipid is DSPG, DPPG, DMPG, PEG-DSPE, or any
combination thereof. The first phospholipid is HSPC, DSPC, DPPC, DMPC or any combination
thereof and the charged lipid is stearylamine, 1,2-dioleoyl-3-trimethylammonium-propane
(DOTAP), 313-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Cholesterol), N4-
Cholesteryl-Spermine (GL67), dimethyldioctadecylammonium (DDAB), 1,2-di-O-octadecenyl-
3-trimethylammonium propane (DOTMA), ethylphosphocholine (ethyl PC) or any combination
thereof.
The teachings of Lenk, Nicolls, and Yang are relied upon as summarized above.
It would have been prima facie obvious to a person of ordinary skill in the art to have
combined the teachings of the patented claims and Lenk, Nicolls, Yang or a combination thereof
in order to arrive at the instantly claimed invention for reasons described above in the
obviousness rejection. One of skill would have been motivated to combine the teachings of
patented claims and prior art references because the references are in the same field of endeavor
as patented claims.
Claims 1-12 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,229,616 B2 in view of Lenk, Nicolls, Yang, individually or in a combination.
Patented claims are drawn to a pharmaceutical 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, wherein the vesicle-forming lipid
consists of a mixture of a first phospholipid selected from the group consisting of
phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic
acid (PA), phosphatidyethanolamine (PE), phosphatidylserine (PS) and any combination thereof
and a second phospholipid selected from the group consisting of a PEG modified phospholipid, a
positively charged or a negatively charged phospholipid, a charged lipid and any combination
thereof; and (b) an internal aqueous medium, comprising 13reprostinil and a salt to provide a pH
gradient between the internal aqueous medium and the external medium, said salt is a weak acid
salt or an amino acid, wherein the weight ratio of 13reprostinil to the at least one vesicle-forming
phospholipid is equal to or higher than about 0.035 and about less than 60% of the 13reprostinil is
released within 2 hours after the administration of the pharmaceutical composition and more than
80% of the 13reprostinil is released more than 2 hours to about 72 hours after the administration of
the pharmaceutical composition. The external lipid bilayer further comprising a sterol selected
from the group consisting of cholesterol, cholesterol hexasuccinate, ergosterol, lanosterol, and
any combination thereof. The weak acid salt is a bicarbonate salt. The first phospholipid is
selected from HSPC, DSPC, DPPC, DMPC or any combination thereof and the second
phospholipid selected from DSPG, DPPG, DMPG, PEG-DSPE, or any combination thereof. The
first phospholipid is selected from HSPC, DSPC, DPPC, DMPC or any combination thereof and
the charged lipid is stearylamine, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 313-
[N-(N’ ,N’ -dimethylaminoethane )-carbamoyl]cholesterol (DC-Cholesterol), N4-CholesterylSpermine (GL67), dimethyldioctadecylammonium (DDAB), 1,2-di-O-octadecenyl-3-
trimethylammonium propane (DOTMA), ethylphosphocholine (ethyl PC) or any combination
thereof.
The teachings of Lenk, Nicolls, and Yang are relied upon as summarized above.
It would have been prima facie obvious to a person of ordinary skill in the art to have
combined the teachings of the patented claims and Lenk, Nicolls, Yang or a combination thereof
in order to arrive at the instantly claimed invention for reasons described above in the
obviousness rejection. One of skill would have been motivated to combine the teachings of
patented claims and prior art references because the references are in the same field of endeavor
as patented claims.
Claims 1-12 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,551,437 B2 in view of Lenk, Nicolls, Yang, individually or in a combination.
Patented claims are drawn to a pharmaceutical composition comprising liposomes, said
liposomes comprising: (a) a lipid bilayer, comprising vesicle-forming lipid; and (b) an internal
aqueous medium inside the lipid bilayer, comprising a bicarbonate salt and a weak acid drug
with a pKa between about 1 to about 6, wherein the liposomes are suspended in an external
medium, the concentration of the bicarbonate salt is about 50 mM to less than about 1000 mM,
the pH of the external medium is above the pKa of the weak acid drug and the vesicle-forming
lipid comprises a mixture of a first phospholipid and a second phospholipid or a mixture of a first
phospholipid and a charged lipid, and wherein the encapsulation efficiency of the weak acid drug
is at least 50%. The first phospholipid is phosphatidylcholine (PC), phosphatidylglycerol (PG),
phosphatidylinositol(PI), phosphatidic acid (PA), phosphatidylethanolamine (PE),
phosphatidylserine (PS) or any combination thereof, the second phospholipid is a PEG modified
phospholipid, a positively charged or a negatively charged phospholipid, and the charged lipid is
a positively charged lipid or a negatively charged lipid. The first phospholipid is HSPC, DSPC,
DPPC, DMPC or any combination thereof and the second phospholipid is DSPG, DPPG,
DMPG, PEG-DSPE, or any combination thereof and the charged lipid is stearylamine, 1,2-
dioleoyl-3-trimethylammonium-propane (DO TAP), 3 ~-[N-(N’ ,N’ -dimethylaminoethane)carbamoyl] cholesterol (DC-Cholesterol), N.sup.4-Cholesteryl-Spermine (GL67), dimethyldioctadecylammonium (DDAB), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), ethylphosphocholine (ethyl PC) or any combination thereof. The vesicle-forming lipid further comprises a sterol that is cholesterol cholesteryl hemisuccinate, ergosterol,
lanosterol, or any combination thereof. The first phospholipid is phosphatidylcholine (PC),
phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic acid (PA),
phosphatidylethanolamine (PE), phosphatidylserine (PS) or any combination thereof, the second
phospholipid is a PEG modified phospholipid, a positively charged or a negatively charged
phospholipid, and the charged lipid is a positively charged or a negatively charged lipid, and the
mole percent of the first phospholipid: cholesterol: the second phospholipid or the charged lipid
is 50-70:20-45:0.1-10. The first phospholipid is HSPC, DSPC, DPPC, DMPC or any
combination thereof, the second phospholipid is DSPG, DPPG, DMPG, PEG-DSPE, or any
combination thereof and the sterol is cholesterol. The first phospholipid is HSPC, DSPC, DPPC,
DMPC or any combination thereof, the charged lipid is stearylamine, 1,2-dioleoyl-3-
trimethylammonium-propane (DOTAP), 3 ~-[N-(N’ ,N’ -dimethylaminoethane )carbamoyl]
cholesterol (DC-Cholesterol), N4-Cholesteryl-Spermine (GL67),
dimethyldioctadecylammonium (DDAB), 1,2-di-O-octadecenyl-3-trimethylammonium propane
(DOTMA), ethylphosphocholine (ethyl PC) or any combination thereof, thereof and the sterol is
cholesterol. The drug is a prostaglandin comprising iloprost and 16reprostinil.
The teachings of Lenk, Nicolls, and Yang are relied upon as summarized above.
It would have been prima facie obvious to a person of ordinary skill in the art to have
combined the teachings of the patented claims and Lenk, Nicolls, Yang or a combination thereof
in order to arrive at the instantly claimed invention for reasons described above in the
obviousness rejection. One of skill would have been motivated to combine the teachings of
patented claims and prior art references because the references are in the same field of endeavor
as patented claims.
Claims 1-12 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,220,483 B2 in view of Lenk, Nicolls, Yang, individually or in a combination.
Patented claims are drawn to a treatment method that requires a pharmaceutical
composition comprising liposomes, said liposomes comprising: (a) a lipid bilayer, comprising
vesicle-forming lipid; and (b) an internal aqueous medium inside the lipid bilayer, comprising a
bicarbonate salt and a weak acid drug with a pKa between about 1 to about 6, wherein the
liposomes are suspended in an external medium, the concentration of the bicarbonate salt is
about 50 mM to less than about 1000 mM, the pH of the external medium is above the pKa of
the weak acid drug and the vesicle-forming lipid comprises a mixture of a first phospholipid and
a second phospholipid or a mixture of a first phospholipid and a charged lipid, and wherein the
encapsulation efficiency of the weak acid drug is at least about 50%. The first phospholipid is
phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic
acid (PA), phosphatidylethanolamine (PE), phosphatidylserine (PS) or any combination thereof,
the second phospholipid is a PEG modified phospholipid, a positively charged or a negatively
charged phospholipid, and the charged lipid is a positively charged or a negatively charged lipid.
The first phospholipid is HSPC, DSPC, DPPC, DMPC or any combination thereof and the
second phospholipid is DSPG, DPPG, DMPG, PEG-DSPE, or any combination thereof and
charged lipid is stearylamine, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 313-[N(
N’,N’-dimethylaminoethane)-carbamoyl]cholesterol (DC-Cholesterol), N.sup.4-CholesterylSpermine (GL67), dimethyldioctadecylammonium (DDAB), 1,2-di-O-octadecenyl-3-
trimethylammonium propane (DOTMA), ethylphosphocholine (ethyl PC) or any combination
thereof. The vesicle-forming lipid further comprises a sterol that is cholesterol, cholesterol
hexasuccinate, ergosterol, lanosterol, or any combination thereof. The first phospholipid is
phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic
acid (PA), phosphatidylethanolamine (PE), phosphatidylserine (PS) or any combination thereof,
the second phospholipid is a PEG modified phospholipid, a positively charged or a negatively
charged phospholipid, and the charged lipid is a positively charged or a negatively charged lipid,
and the mole percent of the first phospholipid: cholesterol: the second phospholipid or the
charged lipid is 50-70:20-45:0.1-10. The first phospholipid is HSPC, DSPC, DPPC, DMPC or
any combination thereof, the second phospholipid is DSPG, DPPG, DMPG, PEG-DSPE, or any
combination thereof and the sterol is cholesterol. The drug is a prostaglandin selected from
iloprost and 17reprostinil.
The teachings of Lenk, Nicolls, and Yang are relied upon as summarized above.
It would have been prima facie obvious to a person of ordinary skill in the art to have
combined the teachings of the patented claims and Lenk, Nicolls, Yang or a combination thereof
in order to arrive at the instantly claimed invention for reasons described above in the
obviousness rejection. One of skill would have been motivated to combine the teachings of
patented claims and prior art references because the references are in the same field of endeavor
as patented claims.
Claims 1-12 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,964,050 B2 in view of Lenk, Nicolls, Yang, individually or in a combination.
Patented claims are drawn to a pharmaceutical composition, comprising liposomes, said
liposomes comprising: (a) a lipid bilayer formed of a first phospholipid, a second phospholipid,
and cholesterol, wherein the first phospholipid is hydrogenated soy phosphatidylcholine (HSPC),
dipalmitoyl phosphatidylcholine (DPPC), distearyloyl phosphatidylcholine (DSPC), diarachidoyl
phosphatidylcholine, dimyristoyl phosphatidylcholine (DMPC) or any combination thereof and
the second phospholipid is distearyloylphosphatidylglycerol (DSPG), or PEG-DSPE; and (b) an
internal aqueous medium inside the lipid bilayer, the internal aqueous medium comprising a
bicarbonate salt with a concentration about 50 mM to about 800 mM and a weak acid drug, said
weak acid drug is iloprost or 18reprostinil, wherein the liposomes are suspended in an external
medium, the pH of the external medium is above the pKa of the weak acid drug and less than
about 7, and wherein the external medium is substantially free of bicarbonate salt such that there
is from less than 2% to 0% bicarbonate salt and the encapsulation efficiency of the weak acid
drug is at least 80%. The claims are further drawn to a lipid bilayer formed of a first
phospholipid, a second phospholipid, and cholesterol, wherein the first phospholipid is
hydrogenated soy phosphatidylcholine (HSPC), dipalmitoyl phosphatidylcholine (DPPC),
distearyloyl phosphatidylcholine (DSPC), diarachidoyl phosphatidylcholine, dimyristoyl
phosphatidylcholine (DMPC) or any combination thereof and the second phospholipid is
distearyloylphosphatidylglycerol (DSPG)or PEG-DSPE; and b. an internal aqueous medium
inside the lipid bilayer, the internal aqueous medium comprising a bicarbonate salt with a
concentration about 200 mM to about 400 mM and prostacyclin, selected from 19reprostinil and
iloprost, wherein the pH of the external medium is above the pK.sub.a of prostacyclin and less
than about 7, and wherein the external medium is substantially free of bicarbonate salt such that
there is from less than 2% to 0% bicarbonate salt.
The teachings of Lenk, Nicolls, and Yang are relied upon as summarized above.
It would have been prima facie obvious to a person of ordinary skill in the art to have
combined the teachings of the patented claims and Lenk, Nicolls, Yang or a combination thereof
in order to arrive at the instantly claimed invention for reasons described above in the
obviousness rejection. One of skill would have been motivated to combine the teachings of
patented claims and prior art references because the references are in the same field of endeavor
as patented claims.
Claims 1-12 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 12,064,406 B2 in view of Lenk, Nicolls, Yang, individually or in a combination.
Patented claims are drawn to a pharmaceutical composition, comprising: liposomes
suspended in an external medium, said liposomes formed from (a) an external lipid bilayer and
(b) an internal aqueous medium, wherein the external lipid bilayer is formed of a mixture of
hydrogenated soy phosphatidylcholine (HSPC), one of distearyloyl phosphatidylglycerol
(DSPG) or PEG-DSPE, and, cholesterol wherein the internal aqueous medium comprising a
weak acid drug selected from 20reprostinil or iloprost and a bicarbonate salt in a concentration of
about 50 mM to about 600 mM to provide a pH of the internal aqueous medium about 7 to 10
and a pH of the external medium that is greater than the pKa of 20reprostinil or the pKa of
iloprost, respectively, and less than 6, wherein the external lipid bilayer has about 75-99 mole %
of the HSPC: about 0-14.9 mole% of cholesterol: about 0.1-25 mole % of DSPG or PEG-DSPE,
and wherein the pharmaceutical composition is characterized by exhibiting a P/T ratio of about 1
to about 100 at least six hours after administering to a subject, where Pis a highest steady state
plasma concentration of the weak acid drug and Tis a lowest steady state plasma concentration
of the weak acid drug, and said PIT ratio indicates that the pharmaceutical composition enhances
the potency of the weak acid drug compared to a free weak acid drug and sustains the therapeutic
effect of the weak acid drug for at least 6 hours. The weak acid drug is iloprost and the PIT ratio
is about 5 to about 40. The weak acid drug is 20reprostinil and the P/T ratio is about 1 to about 20.
The potency of the weak acid drug in the pharmaceutical composition is at least two times more
than that of a free weak acid drug. The external lipid bilayer is formed of a mixture of HSPC,
PEG-DSPE, and cholesterol. The external lipid bilayer is formed of a mixture of HSPC, DSPG,
and cholesterol. The claims are also drawn to a pharmaceutical composition comprising:
liposomes suspended in an external medium, said liposomes formed from (a) an external lipid
bilayer and (b) an internal aqueous medium, wherein the external lipid bilayer is formed of a
mixture of a hydrogenated soy phosphatidylcholine (HSPC) and PEG-DSPE, wherein the
internal aqueous medium comprising iloprost and a bicarbonate salt in a concentration of about
50 mM to about 600 mM to provide a pH of the internal aqueous medium about 7 to 10 and a pH
of the external medium that is greater than the pKa of iloprost, and less than 6, wherein the
external lipid bilayer has about 75-99 mole% of the HSPC: about 0.1-25 mole% of PEG-DSPE,
and wherein the pharmaceutical composition is characterized by exhibiting a P/T ratio of about 1
to about 100 at least six hours after administering to a subject, where Pis a highest steady state
plasma concentration of iloprost and Tis a lowest steady state plasma concentration of iloprost,
and said PIT ratio indicates that the pharmaceutical composition enhances the potency of the
iloprost compared to free iloprost and sustain the therapeutic effect of the iloprost at least 6
hours. The pH of the internal aqueous medium is about 8 to 9. The external lipid bilayer has
about 98 mole% of the HSPC: about 2 mole% of the PEG-DSPE.
The teachings of Lenk, Nicolls, and Yang are relied upon as summarized above.
It would have been prima facie obvious to a person of ordinary skill in the art to have
combined the teachings of the patented claims and Lenk, Nicolls, Yang or a combination thereof
in order to arrive at the instantly claimed invention for reasons described above in the
obviousness rejection. One of skill would have been motivated to combine the teachings of
patented claims and prior art references because the references are in the same field of endeavor
as patented claims.
Response to Arguments
Applicant’s arguments submitted in the remarks dated August 28, 2026 were fully considered but are not persuasive for the following reasons.
Applicant’s statement that Lenk fails to teach the pH of the external medium of above the pKa of the weak acid drug is not persuasive because Lenk teaches a pH range of the external medium in the range of 2.5-4.5. The pKa of Treprostinil is about 3.76 and the pKa of iloprost is about 4.66. The pKa of Treprostinil was obtained from Table 2 on page 590 in Wu (Br J Clin Pharmacol. 2022; 88:587-599). Thus, the claimed pH range is from greater than about 3.76 to less than 7. The ranges overlap, which is sufficient for an obviousness rejection and it is irrelevant that Lenk did not specifically teach a pH range that is greater than a pKa of the drug.
Applicant’s summary of Lenk’s teachings in Table 1 and the conclusion that in order to get 50-100% encapsulation efficiency, the pH of the external medium has to be 1.5-3.5, which is less than the pKa of the claimed drugs, is not persuasive because the applicant is relying on an embodiment when the acidification is performed prior to the dehydration or lyophilization. In the same section in lines 44-50, Lenk teaches an embodiment where the acidification is performed subsequent to the dehydration or lyophilization, the rehydration is performed using an aqueous solution at pH about 2.5 to about 4.5, and without the drying protectant. This latter method, i.e., acidifying the solution after the drying step, is preferred. Addition of the drying protectant is not limited to the section cited by the applicant. There is no teaching in Lenk that the pH is required to be 1.5-3.5 in embodiments when a drying protectant is used in order to achieve 50-100% encapsulation. Even Lenk’s claims describe the external medium as having a pH in the range of 2.5-4.5.
There is no teaching in Lenk that requires an encapsulation efficiency of 30% and less to be associated with an external pH being less than the pKa of the drug. It is not relevant that Lenk does not recognize a relationship between the pH of the external medium, the drug pKa, and the encapsulation efficiency. Lenk teaches pH ranges that overlap with the instantly claimed pH ranges, which is sufficient for an obviousness rejection. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
It is also noted that the instant claims are drawn to a product and not to a method of making the product, and that the encapsulation efficiency is not a claimed limitation. Even if Lenk teaches embodiments of methods that result in an encapsulation efficiency that is not preferred, those embodiments may still be applied in the rejection because instant claims are not drawn to an encapsulation method that is required to have a certain encapsulation efficiency.
A reference is not required to teach examples for an obviousness rejection to be proper.
The data submitted in the declaration is not sufficient to obviate the grounds of rejection because applicant showed that liposomal formulations having a pH value (3.0) of the external medium that is outside the claimed range have properties that are different than liposomal formulations having a pH (5.5) of the external medium that is encompassed by the claimed pH range. Applicant formed two sets of liposomal formulations where the liposomal formulations in each set are identical except for the pH in the external medium. One formulation has a pH of 3.0 in the external medium and the other formulation has a pH of 5.5 in the external medium. Applicant stated that the pH of 3.0 was selected because the liposomal formulation in Lenk’s example 1 has a pH of 3.0. However, Lenk is not limited by the single pH of 3.0. Lenk teaches a pH range of 2.5-4.5 that is suitable for the external medium. The applicant did not show that the claimed pH range of the external medium is critical and would produce the same result as the tested formulation having a pH of 5.5 in the external medium because applicant tested a single pH value without showing that the data obtained for a pH of 5.5 can be extrapolated to the entire range. Similarly, the applicant did not show that the result obtained for a formulation having a pH of 3.0 in the external medium can be extrapolated to show that Lenk’s entire pH range of 2.5-4.5 would produce the same result as pH 3.0.
It is noted that the examiner found a reference by Wu which teaches that the pKa of Treprostinil is 3.76, and the references the applicant provided teaches the pKa of 4.5. For the purpose of applying prior art, the pH range of the external medium is given the broadest reasonable range, that is greater than 3.76 and less than 7. The claims do not require any conditions under which the pKa of the acidic drug is measured, thus it would have been reasonable to interpret the claim to encompass the broadest reasonable pH.
The applicant stated that the observed results are unexpected. This argument is not found persuasive because applicant has not met the requirements set forth in MPEP 716.02.
The claims are not commensurate in scope with the examples that produced the asserted unexpected properties. The applicant did not show that the observed results for the two examples can be extrapolated and expected to occur over the entire breadth of the claimed compositions. The applicant did not show that the claimed pH range of the external medium is critical because the applicant only tested a single pH value of 5.5, whereas the range spans from 3.76 and up to 7. It is also noted that the pKa of Treprostinil cited by applicant is 4.5, whereas the examiner found a reference by Wu which teaches a pKa of 3.76. To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
Double patenting rejections are maintained because applicant requested the rejections to be held in abeyance.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALMA PIPIC/Primary Examiner, Art Unit 1617
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