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 .
Supplemental Amendment
The supplemental amendment filed 02/24/2026 in response to the Notice of Non-Compliant Amendment mailed 02/13/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of the species of (a) a method of increasing the delivery of oxygen in a subject and (b) conditions the aqueous solution must satisfy of one or more administered fixed dose of the aqueous solution comprises a liposome encapsulating calcium trans-crocetinate (CTC)); wherein the liposome comprises HSPC, and has a diameter of 80 nm to 120 nm and a zeta potential of 25 to 0 mV, and wherein the trans-crocetin/lipid ratio in the aqueous solution is 20 to 120 g/mM in the reply filed on 01/20/2026 is acknowledged.
The Examiner notes that the elected condition of trans-crocetin/lipid ratio recites units of g/mM, while claim 192 recites units of g/M and g/mol. Thus, the election of trans-crocetin/lipid ratio is being rejoined with those recited in “[e]” of claim 192.
Claims 202-204 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/20/2026.
Claims 187-201 and 205-207 are under current examination.
Priority
This application is a national stage entry of PCT/US2021/026532, filed 04/09/2021. Priority has been claimed to US PRO 63/150,538, filed 02/17/2021, US PRO 63/071,338, filed 08/27/2020, US PRO 63/071,312, filed 08/27/2020, US PRO 63/064,300, filed 08/11/2020, and US PRO 63/057,203, filed 07/27/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/22/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
The information disclosure statement submitted on 01/21/2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because no copy of NPL Citation No. 9 (“KOPEC et al.”) has been provided, and thus the reference was not considered. The remainder of the IDS filed 01/21/2026 has been considered by the Examiner.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 187 is objected to because of the following informalities: for consistency in the claim language, it is suggested that “the one or more administered dose(s)” in line 5 should read “the one or more administered dose”. It is further suggested that the (i) in “Q is (i) a multivalent cation counterion” be omitted.
Claim 191 is objected to because of the following informalities: the closing parenthesis in line 4 and the opening parenthesis in line 9 should be omitted. It is further suggested that “having and have a zeta potential” in lines 6 and 10, respectively, should read “having a zeta potential”.
Claim 192 is objected to because of the following informalities: the closing parenthesis in line 3 of “[m]” should be omitted, and it is suggested that “00.2” in line 2 of “[m]” should read “0.2”. It is further suggested that the chemical names for the abbreviated lipids (such as DSPE) in “[h]” and “[i]” be recited upon their first occurrence.
Claim 194 is objected to because of the following informalities: it is suggested that “having and have a zeta potential” in lines 8 and 12, respectively, should read “having a zeta potential”.
Claim 196 is objected to because of the following informalities: for consistency in the claim language, it is suggested that “one or more fixed loading dose(s)” in line 2 should read “one or more fixed loading dose”.
Claim 197 is objected to because of the following informalities: it is suggested that “having and have a zeta potential” in lines 8 and 12, respectively, should read “having a zeta potential”.
Claim 198 is objected to because of the following informalities: for consistency in the claim language, it is suggested that “two or more fixed maintenance dose(s)” in line 2 should read “two or more maintenance doses”.
Claim 201 is objected to because of the following informalities: it is suggested that “having and have a zeta potential” in lines 8 and 12, respectively, should read “having a zeta potential”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 187-201 and 207 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for increasing the delivery of oxygen in a subject, does not reasonably provide enablement for treating or preventing any disease or condition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. MPEP 2164.01(a), citing In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), sets out the factors to consider whether experimentation is undue, which include:
(A) The breadth of the claims. The claims recite a method of treating or preventing a disease or condition in a patient comprising administering an effective amount of liposomal trans-crocetin; the claims do not limit the disease or condition. Absent a limiting definition in the instant specification, preventing a disease or condition is suggested to include a level of protection against, up to and including complete protection against the development of any disease or condition, which is unsupported by the disclosure. Giving the claims their broadest reasonable interpretation, prevention includes any measure taken prior to the onset or occurrence of which precludes its coming into existence, absolutely and in all cases. Therefore, preventing any disease or condition renders the scope of the claims unreasonably broad.
(B) The nature of the invention. The claims are drawn to a method of treating or preventing a disease or condition in a patient comprising administering an effective amount of liposomal trans-crocetin. The instant specification states, “Terms such as "treating," or "treatment," or "to treat" refer to both (a) therapeutic measures that cure, slow down, attenuate, lessen symptoms of, and/or halt progression of a diagnosed pathologic disorder or condition and (b) prophylactic or preventative measures that prevent and/or slow the development of a targeted disorder or condition” (paragraph [0067]). The claims do not limit the disease or condition, and the instant specification provides a vast and wide-ranging number of conditions including ischemia, infection, diabetes, cancer, asthma, Alzheimer’s disease, etc. (see particularly paragraphs [0067] and [0301]-[0320]).
(C) The state of the prior art. It is known in the prior art that not every condition or disease can be prevented. As just a limited number of examples, the prior art of Lakeridge Health teaches that asthma cannot be prevented from starting (“Asthma Attack Prevention”, pg. 1); the prior art of Harris teaches that “outright prevention of Type 1 diabetes isn’t possible” (“An Experimental Genetic Test Gives Early Warning for Kids at Risk of Type 1 Diabetes”, pg. 2); and the prior art of Park teaches that while we can take measures to protect ourselves from certain cancers, some cancers are hereditary, and “some tumors emerge simply at random” (“Most Cancer is Beyond Your Control, Breakthrough Study Finds”, pg. 1).
(D) The level of one of ordinary skill. The level of ordinary skill in the art is assumed to be that
of one having knowledge and/or experience in the medical field of disease or condition treatment. While the relative skill of those in the art is high, likely that of an MD or Ph.D., that factor is outweighed by the unpredictable nature of the art.
(E) The level of predictability in the art. “Preventing” connotes an absolute absence of a
condition which cannot reasonably be achieved with regard to medicine generally, with few exceptions
(such as vaccines to prevent the development of pathogen-borne illnesses). As noted above, the prior
art teaches that not every disease or condition can be prevented. The prior art further suggests that even when protective measures are taken, some diseases such as cancer occur due to hereditary or even random causes (see Park, “Most Cancer is Beyond Your Control, Breakthrough Study Finds”, pg. 1).
Even if a patient can be identified as having a risk factor for a disease or condition, there is no certainty that failure to develop that disease or condition can reliably be attributed to the claimed administering of a fixed dose of liposomal trans-crocetin. In this sense, in the context of preventing any disease or condition, the level of unpredictability is extremely high.
(F) The amount of direction provided by the inventor. The working examples in the specification demonstrate the treatment of severe grade sepsis and acute respiratory distress syndrome due to COVID-19 (paragraphs [0391]-[0444]). The specification does not provide direction or guidance for practicing the claimed invention in its “full scope”. No reasonably specific guidance is provided concerning useful therapeutic protocols for preventing or treating all diseases or conditions, other than those of the working examples.
(G) The existence of working examples. As noted above, the working examples in the specification demonstrate the treatment of severe grade sepsis and acute respiratory distress syndrome due to COVID-19 (paragraphs [0391]-[0444]). No reasonably specific guidance is provided concerning useful therapeutic protocols for preventing or treating all diseases or conditions, and the results of the working examples are not such that a skilled artisan would understand that these results extend to the prevention or treatment of any disease or condition.
(H) The quantity of experimentation needed to make or use the invention. Because prevention
of every disease or condition cannot be achieved with any certainty, coupled with a lack of evidence in
the working examples that the claimed method is capable of treating or preventing any disease or condition, a skilled artisan could not practice the method of increasing the delivery of oxygen or treating or preventing a disease or condition in a subject commensurate with the full scope of the claims without undue experimentation.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 188-201 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance:
claim 188 recites the broad recitation “in an amount of 60mg to 600mg”, and the claim also recites “or 100mg to 400mg” which is the narrower statement of the range/limitation; similar broad/narrow recitations of the amounts of administered doses are recited in claims 189, 190, 196, and 198;
claim 191 recites the broad recitation “having a diameter of 80 nm to 120 nm”, and the claim also recites “90 nm to 110 nm, or 95 nm to 109 nm” in lines 2-3 and “(80 nm to 120 nm, 90 nm to 110 nm, or 95 nm to 109” in lines 9-10, which is the narrower statement of the range/limitation; claim 191 further recites “a zeta potential of -15 to -1 mV”, and the claim also recites “-10 to -1 mV, or -5 to -1 mV” in lines 6 and 10-11, which is the narrower statement of the range/limitation; similar broad/narrow recitations of diameter and zeta potential are recited in claims 192, 194, 197, and 201;
claim 192 further recites the broad recitation in [e] “about 10 to 150 g/mol”, and the claim also recites “about 20 to 100 g/mol” which is the narrower statement of the range/limitation; claim 192 recites in [r] the broad limitation “which has a pH of 5-8”, and the claim also recites “or a pH of 6-7” which is the narrower statement of the range/limitation; claim 192 recites in [s] the broad limitation “the liposome comprises 10 to 100,000…molecules of trans-crocetin”, and the claim also recites “100 to 10,000, or 500 to 5,000 molecules of trans-crocetin” which is the narrower statement of the range/limitation; claim 192 recites in [t] the broad limitations “the trans-crocetin/lipid ratio is 20 to 120 g/mM” and the claim also recites “about 25 to 100 g/mM” which is the narrower statements of the range/limitations, respectively; claim 192 recites in [u] the broad limitation “the PDI is 0.020 to 0.075”, and the claim also recites “or 0.030 to 0.050” which is the narrower statement of the range/limitation;
claim 193 recites the broad recitation “1 hour to 48 hours”, and the claim also recites “1.5 hours to 24 hours, 2 hours to 18 hours, 4 hours to 16 hours (e.g., 12 hours(+/- 3 hours)), or 1 hour to 8 hours (e.g., 3 hours) apart”, which is the narrower statement of the range/limitation; similar broad/narrow recitations of the times of administered doses are recited in claims 195, 196, and 200;
The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 199 is rejected under 35 U.S.C. 112(b) by virtue of its dependency on indefinite claim 197 and failure to cure the deficiency noted above.
The metes and bounds of claim 192 are uncertain. The claim recites a series of multiply dependent limitations, and recites “and/or [u] the aqueous solution according to any one of [a] to [t]”, indicating that all conditions [a]-[u] may be present. However, this creates indefiniteness, at least because the claim recites both “wherein the liposome is anionic or neutral” in “[j]” and also recites “wherein the liposome is cationic” in “[n]”, which cannot both be true. Similar to the requirement that multiple dependent claims be in the alternative form (see MPEP 608.01(n)), the Examiner suggests that the claim be rewritten so that a multiple dependent limitation does not serve as a basis for any other multiple dependent limitation.
Claim 192 in “[e]” recites “the trans-crocetin/lipid ratio is 1 to 1000 g/M, about 10 to 150 g/mol, about 20 to 100 g/mol, or any range therein between”; the metes and bound of this limitation are uncertain. It is first unclear if Applicant intends to recite different units “g/M” and “g/mol” or if these are intended to be the same. The scope of the claimed ratios is further uncertain; for example, does “10 to 150 g/mol” indicate (a) a range of 10 g of trans-crocetin:1 mol of lipid to 150 g trans-crocetin:1 mol of lipid or (b) 10 g/mol of trans-crocetin:150 g/mol lipid?
Further regarding claim 192, the phrase "such as" in “[i] the aqueous solution according to any one of [a] to [h] where in the liposome comprises an oxidized phospholipid such as on OxPAPC” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Further regarding claim 193, the phrase “e.g.” in "(e.g., 12 hours (+/- 3hours)) and "(e.g., 3 hours)” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Further regarding claims 195, 196, and 200, the recitation of “(+/- 3 hours)” in parentheses renders the claims indefinite because it is unclear whether the limitations in parentheses are required or not. If Applicant intends for this to be a required limitation, it is recommended that the parentheses be removed.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 187-191, 193-201, and 205-207 are rejected under 35 U.S.C. 103 as being unpatentable over Gao (US 2016/0199398 A1, published July 14, 2016, included on IDS submitted 01/21/2026) as evidenced by Li et al. (“Hypoxia-Induced Oxidative Stress in Ischemic Retinopathy” Oxidative Medicine and Cellular Longevity 2012, Article ID 426769), hereafter “Li”, in view of Lockwood et al. (US 2007/0015735 A1, published January 18, 2007; included on IDS submitted 09/22/2023), hereafter “Lockwood”, and Hoarau et al. (US 2004/0076683 A1, published April 22, 2004; included on IDS submitted 01/21/2026), hereafter “Hoarau”.
Regarding instant claims 187 and 205, Gao teaches compositions containing crocetin for prevention and/or treatment of cancers and other conditions and diseases (abstract, claim 1) and a method of preventing, mitigating, or treating a disease or condition in a subject comprising administering an effective amount of the composition to a subject in need thereof (claim 11). Gao exemplifies the structure of alpha-crocetin, which is in the trans configuration (see paragraphs [0005]-[0006]). Gao teaches that compositions may be administered in the form of liposomes (paragraph [0104]) and that crocetin may be in a dose of about 50 mg to about 500 mg per dose (paragraph [0105]). Compositions for oral administration can be prepared in water or other aqueous vehicles (paragraph [0099], and compositions can comprise pharmaceutically acceptable sterile aqueous solution, dispersions, etc. (paragraphs [0100]). Gao teaches that the method improves eye health, increases blood flow to the retina, and prevents ischemic retinopathy (claim 24, paragraph [0037]). As the method of Gao is taught to increase blood flow and prevent an ischemic condition, it is interpreted that the method of Gao increases the delivery of oxygen; per the instant specification, “’Ischemia’ relates to a restriction in blood supply to tissues or organs (tissue hypoperfusion) causing a shortage of oxygen needed for cellular metabolism” (paragraph [0063]).
Regarding instant claims 188-189, as noted above, Gao teaches administering a dose of about 50 mg to about 500 mg (paragraph [0105]), overlapping the claimed ranges. Per MPEP 2144.05 I., “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
Regarding instant claim 190, 193, 195, and 196, as noted as noted above, Gao teaches administering a dose of about 50 mg to about 500 mg (paragraph [0105]), overlapping the claimed ranges. Gao further teaches that in certain embodiments, more than one dose is administered (e.g., two or more doses spaced over time) (paragraph [0094]), and that the dose and dose frequency can vary according to the age, body weight, and conditions of an individual patient (paragraph [0105]). Gao further teaches that daily doses can be in single or divided doses (paragraph [0106]).
Regarding instant claims 198-201, as noted above, Gao teaches administering a dose of about 50 mg to about 500 mg (paragraph [0105]), overlapping the claimed ranges, that more than one dose is administered (e.g., two or more doses spaced over time) (paragraph [0094]), that the dose and dose frequency can vary according to the age, body weight, and conditions of an individual patient (paragraph [0105]), and that daily doses can be in single or divided doses (paragraph [0106]). These daily doses are interpreted to meet the limitation of “fixed maintenance doses”.
Regarding instant claim 206, as the method of Gao is taught to improve eye health, increase blood flow, and prevent an ischemic condition, it is interpreted that the method increases the physical performance of the subject treated and that the subject is in need of increased blood flow (increased oxygen delivery).
Gao does not teach a multivalent cation counterion, as required by instant claim 187.
Lockwood teaches carotenoid derivatives and their administration for reducing a subject’s risk of experiencing diseases associated with reactive oxygen species (abstract) including pharmaceutically acceptable salts such as calcium, magnesium, etc. (paragraphs [0094]-[0095]); the administration can inhibit and/or ameliorate disease conditions associated with inhibition of vision (paragraph [0020]). Compounds may be administered in the form of liposome delivery systems (paragraph [0208]). Carotenoids can be modified to enhance the water solubility (abstract, paragraph [0020], paragraph [0114]), including by transforming into a salt derivative or analog (paragraph [0180]).
It would have prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the trans-crocetin in the method of Gao with the multivalent cation counterion suggested by Lockwood. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success to improve the water solubility of trans-crocetin, a carotenoid (see Gao, paragraph [0005]), for use in liposomal formulations for reducing a subject’s risk of experiencing diseases associated with reactive oxygen species, such as those associated by inhibition of vision, as suggested by Lockwood. There is a reasonable expectation of success as Gao teaches administration of aqueous and liposomal formulations of trans-crocetin for increasing blood flow to the retina and preventing ischemic retinopathy. As evidenced by Li, oxidative stress, or the imbalance between the production of reactive oxygen species and the ability to scavenge these, plays a crucial role in the pathogenesis of retinal ischemia (see entire document, particularly abstract).
Gao does not teach that the liposome is pegylated or a has a diameter of 20 nm to 200 nm, as required by instant claim 187, nor the diameters of instant claims 191, 194, 197, and 201.
Hoarau teaches stealth lipid nanocapsules used as a carrier for active principles including carotenoids (abstract, claims 1 and 33-35). The nanocapsules include at least one amphiphilic derivative of poly(ethylene glycol) (abstract) such as pegylated phospholipids (paragraphs [0086]-[0093]); the “pegylated” derivative confers a stealth aspect which allows the nanocapsules to not be detected and then sequestered and/or degraded by the immune system of the host to which they are administered (see paragraphs [0001]-[0002], [0006], and [0011]-[0012]). Hoarau teaches diameters between 80 and 120 nm in diameter (claims 26-27) and that sizes less than 200 nm avoid extravasation at the level of cells of the liver, avoid filtration in the spleen, and increase the amount of time in blood circulation (paragraph [0065]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the liposomes in the method of Gao with the pegylation and diameter of 80 nm-120 nm, overlapping the ranges of the instant claims, suggested by Hoarau. One of ordinary skill in the art would have been motivated to do so in order to achieve a carrier for the delivery of a carotenoid active agent with stealth properties which avoids immune detection and degradation, and which is in a size that increases the amount of time in blood circulation, as suggested by Hoarau. There is a reasonable expectation of success as Gao teaches liposomal formulations for the delivery of trans-crocetin, a carotenoid, (see Gao, paragraph [0005]), and suggests that the liposomes can comprise physiologically acceptable phospholipids known in the art (paragraph [0104]).
Regarding instant claim 207, the limitation “liposomes in at least one administered dose of liposomal trans-crocetin are prepared according to a method comprising…” is a product-by-process limitation. Per MPEP 2113, "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
Here, the liposome defined by the process of claim 207 is that which is structurally defined in claim 187; that is, a pegylated liposome encapsulating trans-crocetin having the formula Q-trans-crocetin-Q, wherein, Q is a multivalent cation counterion, and the liposome diameter is 20 nm to 200 nm, or any range therein between. As set forth above, the prior art of Gao in view of Lockwood and Hoarau renders obvious the method of claim 187 and structural limitations of the liposome of claim 187, and thus renders obvious the method of administering the liposome made by the process of the instant claim.
Claim 192 is rejected under 35 U.S.C. 103 as being unpatentable over Gao, as evidenced by Li, in view of Lockwood and Hoarau as applied to claims 187-191, 193-201, and 205-207 above, and further in view of de Sousa Martins (US 2017/0231920 A1, published August 17th, 2017).
The teachings of the modified Gao are set forth above. Regarding the elected species of claim 192, as set forth above, the modified Gao teaches a multivalent cation counterion including calcium, and the elected 80 nm to 120 nm liposome diameter. Regarding the elected species that the liposome comprises HSPC, Hoarau further teaches the inclusion of HSPC to obtain benefits such as better rigidity and stealth properties (paragraph [0073]), rendering the inclusion of HSPC in the liposomes of Gao prima facie obvious to one of ordinary skill in the art, particularly as Gao suggests that the liposomes can comprise physiologically acceptable phospholipids known in the art (paragraph [0104]).
As noted above, the trans-crocetin/lipid ratio recited in “[e]” of claim 192 is indefinite. However, Gao teaches administering an effective amount of trans-crocetin (paragraph [0094]) in a dose consistent with that of the instant invention, and administration via liposomes comprising lipids (paragraph [0104]). Gao further suggests modifying the dose of crocetin according to the individual needs of a patient (paragraph [0105]). Thus, one of ordinary skill in the art would have been motivated to routinely optimize the concentration of trans-crocetin, and thus the corresponding ratio of trans-crocetin to lipid, in order to achieve a dosage that is effective for the age, body weight, and condition of an individual patient. Per MPEP 2144.05 II. A., “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
The combination of Gao, Lockwood, and Hoarau do not teach the elected species limitation of a zeta potential of 25 to 0 mV.
de Sousa Martins teaches positively charged liposome vesicles for use as carriers of lipophilic molecules, particularly carotenoids (abstract, claims 1 and 3). The liposomes are capable of transporting the lipophilic molecules through the cornea and sclera cells for delivery to the eye (paragraphs [0002] and [0005]). de Sousa Martins exemplifies a cationic liposomal formulation with a zeta potential of +3.64 mV) (paragraph [0033], Fig. 9).
It would have prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the liposome in the method of the modified Gao with the zeta potential consistent with the elected species suggested by de Sousa Martins. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success to achieve a positively charged liposome capable of delivering carotenoids to ocular tissue, as suggested by de Sousa Martins. There is a reasonable expectation of success as Gao teaches administration of liposomal formulations of trans-crocetin, a carotenoid (see Gao, paragraph [0005]), for increasing blood flow to the retina (an ocular tissue) and preventing ischemic retinopathy.
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.
Claims 187-201 and 205-207 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 187-190, 193-199, and 203-207 of copending Application No. 18/018,132 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Both the instant claims and those of copending Application No. 18/018,132 are directed to a method of increasing the delivery of oxygen comprising administering one or more fixed dose of liposomal trans-crocetin in an aqueous solution. Both sets of claims recite Q-trans-crocetin-Q, wherein Q is a multivalent cation counterion, and recite a pegylated liposome. Both sets of claims recite dosage amounts, liposome diameters, zeta potentials, trans-crocetin/lipid ratios, and times of dosage administration in overlapping amounts. Both sets of claims recite the same subject population (compare instant claim 206 to copending claim 204), and that the liposomes are made via the same method (compare instant claim 207 to copending claim 205).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 187-201 and 205-207 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 188-205, and 209-211 of copending Application No. 17/917,792 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Both the instant claims and those of copending Application No. 17/917,792 are directed to a method of increasing the delivery of oxygen comprising administering one or more fixed dose of liposomal trans-crocetin in an aqueous solution. Both sets of claims recite Q-trans-crocetin-Q, wherein Q is a multivalent cation counterion, and recite a pegylated liposome. Both sets of claims recite dosage amounts, liposome diameters, zeta potentials, trans-crocetin/lipid ratios, and times of dosage administration in overlapping amounts. Both sets of claims recite the same subject population (compare instant claim 206 to copending claim 210), and that the liposomes are made via the same method (compare instant claim 207 to copending claim 211).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 187-201 and 205-207 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 188-198, 200-206, 213, and 215-219 of copending Application No. 17/917,908 in view of Gao (US 2016/0199398 A1, published July 14, 2016, included on IDS submitted 01/21/2026).
Both the instant claims and those of copending Application No. 17/917,908 are directed to a method of increasing the delivery of oxygen comprising administering one or more fixed dose of liposomal trans-crocetin. Both sets of claims recite Q-trans-crocetin-Q, wherein Q is a multivalent cation, and recite a pegylated liposome. Both sets of claims recite liposome diameters, zeta potentials, trans-crocetin/lipid ratios, and times of dosage administration in overlapping amounts. Both sets of claims recite the same subject population (compare instant claim 206 to copending claim 213). While the copending claims do not teach that the liposomes are made by the method recited in instant claim 207, this is a product-by-process limitation that does not structurally limit the liposomes administered in the method.
The claims of copending Application 17/917,908 recite dosage amounts in mg/kg, while the instant claims recite dosage amounts in mg (50mg to 900mg in instant independent claim 187). The claims of copending Application 17/917,908 do not recite that the liposomes are in an aqueous solution.
Gao teaches compositions containing crocetin for prevention and/or treatment of cancers and other conditions and diseases (abstract, claim 1) and a method of preventing, mitigating, or treating a disease or condition in a subject comprising administering an effective amount of the composition to a subject in need thereof (claim 11). Gao exemplifies the structure of alpha-crocetin, which is in the trans configuration (see paragraphs [0005]-[0006]). Gao teaches that compositions may be administered in the form of liposomes (paragraph [0104]) and that crocetin may be in a dose of about 50 mg to about 500 mg per dose (paragraph [0105]). Gao further teaches the dose and dose frequency can vary according to the age, body weight, and conditions of an individual patient (paragraph [0105]). Compositions for oral administration can be prepared in water or other aqueous vehicles (paragraph [0099], and compositions can comprise pharmaceutically acceptable sterile aqueous solution, dispersions, etc. (paragraphs [0100]). Gao teaches that the method improves eye health, increases blood flow to the retina, and prevents ischemic retinopathy (claim 24, paragraph [0037]).
It would have been prima facie obvious to one of ordinary skill in the art to modify the doses of trans-crocetin recited in copending Application No. 17/917,908 with the dose suggested by Gao, overlapping that of the instant claims, in order to optimize the dose to one that is suitable for the age, weight, and condition of the individual patient. It would further have been prima facie obvious to incorporate the liposomes into an aqueous solution, as suggested by Gao, in order to use a pharmaceutically acceptable solvent that can deliver the liposomal formulation by a desired route.
This is a provisional nonstatutory double patenting rejection.
Claims 187-201 and 205-207 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 13, 20, 33-34, 39, and 66-67 of copending Application No. 18/559,680 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of copending Application No. 18/559,680 are directed to a method of treating a chronic disease in a subject, including chronic hypoxia; thus, the method is interpreted as increasing the delivery of oxygen and that the subject is in need of increased oxygen delivery. Both the method of the instant claims and that of copending Application No. 18/559,680 recite administering one or more fixed dose of liposomal trans-crocetin in an aqueous solution. Both sets of claims recite Q-trans-crocetin-Q, wherein Q is a multivalent cation counterion, and a pegylated liposome. Both sets of claims recite dosage amounts, liposome diameters, zeta potentials, trans-crocetin/lipid ratios, and times of dosage administration in overlapping amounts. While the copending claims do not teach that the liposomes are made by the method recited in instant claim 207, this is a product-by-process limitation that does not structurally limit the liposomes administered in the method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 187-201 and 205-207 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 188-198, 200-206, 213, and 215-219 of copending Application No. 17/917,908 in view of Gao (US 2016/0199398 A1, published July 14, 2016, included on IDS submitted 01/21/2026).
Both the instant claims and those of copending Application No. 17/917,908 are directed to a method of increasing the delivery of oxygen comprising administering one or more fixed dose of liposomal trans-crocetin. Both sets of claims recite Q-trans-crocetin-Q, wherein Q is a multivalent cation, and recite a pegylated liposome. Both sets of claims recite liposome diameters, zeta potentials, trans-crocetin/lipid ratios, and times of dosage administration in overlapping amounts. Both sets of claims recite the same subject population (compare instant claim 206 to copending claim 213). While the copending claims do not teach that the liposomes are made by the method recited in instant claim 207, this is a product-by-process limitation that does not structurally limit the liposomes administered in the method.
The claims of copending Application 17/917,908 recite dosage amounts in mg/kg, while the instant claims recite dosage amounts in mg (50mg to 900mg in instant independent claim 187). The claims of copending Application 17/917,908 do not recite that the liposomes are in an aqueous solution.
Gao teaches compositions containing crocetin for prevention and/or treatment of cancers and other conditions and diseases (abstract, claim 1) and a method of preventing, mitigating, or treating a disease or condition in a subject comprising administering an effective amount of the composition to a subject in need thereof (claim 11). Gao exemplifies the structure of alpha-crocetin, which is in the trans configuration (see paragraphs [0005]-[0006]). Gao teaches that compositions may be administered in the form of liposomes (paragraph [0104]) and that crocetin may be in a dose of about 50 mg to about 500 mg per dose (paragraph [0105]). Gao further teaches the dose and dose frequency can vary according to the age, body weight, and conditions of an individual patient (paragraph [0105]). Compositions for oral administration can be prepared in water or other aqueous vehicles (paragraph [0099], and compositions can comprise pharmaceutically acceptable sterile aqueous solution, dispersions, etc. (paragraphs [0100]). Gao teaches that the method improves eye health, increases blood flow to the retina, and prevents ischemic retinopathy (claim 24, paragraph [0037]).
It would have been prima facie obvious to one of ordinary skill in the art to modify the doses of trans-crocetin recited in copending Application No. 17/917,908 with the dose suggested by Gao, overlapping that of the instant claims, in order to optimize the dose to one that is suitable for the age, weight, and condition of the individual patient. It would further have been prima facie obvious to incorporate the liposomes into an aqueous solution, as suggested by Gao, in order to use a pharmaceutically acceptable solvent that can deliver the liposomal formulation by a desired route.
Given the subject matter of the instant claims is obvious and substantially overlaps the subject matter of copending Application No. 17/917,908, the instant claims are rejected on the ground of nonstatutory double patenting. This is a provisional nonstatutory double patenting rejection.
Claims 187-201 and 205-207 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 123-135 and 138-139 of copending Application No. 19/333,941 in view of Gao (US 2016/0199398 A1, published July 14, 2016, included on IDS submitted 01/21/2026).
The claims of copending Application No. 19/333,941 are directed to a method of treating a disease or condition characterized by ischemia or hypoxia (see copending claims 138-139); thus, the method is interpreted as increasing the delivery of oxygen and that the subject is in need of increased oxygen delivery. Both the instant claims and those of copending Application No. 19/333,941 recite administering a pegylated liposome encapsulating Q-trans-crocetin-Q, wherein Q is a multivalent cation counterion, with overlapping diameters of liposome. The claims of copending Application No. 19/333,941 further recite liposomes that have zeta potentials and trans-crocetin/lipid ratios in overlapping amounts. While the copending claims do not teach that the liposomes are made by the method recited in instant claim 207, this is a product-by-process limitation that does not structurally limit the liposomes administered in the method.
The claims of copending Application 19/333,941 do not recite the fixed dose amounts (50mg to 900mg in instant independent claim 187) nor dosing times recited by the instant claims. The claims of copending Application 19/333,941 do not recite that the liposomes are in an aqueous solution.
Gao teaches compositions containing crocetin for prevention and/or treatment of cancers and other conditions and diseases (abstract, claim 1) and a method of preventing, mitigating, or treating a disease or condition in a subject comprising administering an effective amount of the composition to a subject in need thereof (claim 11). Gao exemplifies the structure of alpha-crocetin, which is in the trans configuration (see paragraphs [0005]-[0006]). Gao teaches that compositions may be administered in the form of liposomes (paragraph [0104]) and that crocetin may be in a dose of about 50 mg to about 500 mg per dose (paragraph [0105]). Gao further teaches that in certain embodiments, more than one dose is administered (e.g., two or more doses spaced over time) (paragraph [0094]), and that the dose and dose frequency can vary according to the age, body weight, and conditions of an individual patient (paragraph [0105]). Gao further teaches that daily doses can be in single or divided doses (paragraph [0106]). Compositions for oral administration can be prepared in water or other aqueous vehicles (paragraph [0099], and compositions can comprise pharmaceutically acceptable sterile aqueous solution, dispersions, etc. (paragraphs [0100]). Gao teaches that the method improves eye health, increases blood flow to the retina, and prevents ischemic retinopathy (claim 24, paragraph [0037]).
It would have been prima facie obvious to one of ordinary skill in the art to modify the method of administering liposomal trans-crocetin recited in copending Application No. 19/333,941 with the dose and dose frequency suggested by Gao, overlapping that of the instant claims. One of ordinary skill in the art would have been motivated to do so in order to optimize the dose and frequency to one that is suitable for treating ischemic conditions and which is suitable for the age, weight, and condition of the individual patient. It would further have been prima facie obvious to incorporate the liposomes into an aqueous solution, as suggested by Gao, in order to use a pharmaceutically acceptable solvent that can deliver the liposomal formulation by a desired route.
Given the subject matter of the instant claims is obvious and substantially overlaps the subject matter of copending Application No. 19/333,941, the instant claims are rejected on the ground of nonstatutory double patenting. This is a provisional nonstatutory double patenting rejection.
Claims 187-201 and 205-207 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8-10, 29, 31, 35, 45, 50-51, 58-59, and 80-81 of copending Application No. 19/339,809 in view of Gao (US 2016/0199398 A1, published July 14, 2016, included on IDS submitted 01/21/2026).
The claims of copending Application No. 19/339,809 are directed to a method of treating a disease or condition characterized by ischemia or hypoxia (see copending claims 80-81); thus, the method is interpreted as increasing the delivery of oxygen and that the subject is in need of increased oxygen delivery. Both the instant claims and those of copending Application No. 19/339,809 recite administering a liposome encapsulating Q-Polyene Carotenoid-Q, wherein Q is a multivalent cation counterion, with overlapping diameters of liposome. The claims of copending Application No. 19/339,809 further recite that the liposome encapsulates Q-trans-crocetin-Q, that the liposome comprises pegylated lipids, that the liposome is in an aqueous pharmaceutically acceptable carrier, and liposomes that have zeta potentials, diameter, and carotenoid/lipid ratios in overlapping amounts with those of the instant claims. While the copending claims do not teach that the liposomes are made by the method recited in instant claim 207, this is a product-by-process limitation that does not structurally limit the liposomes administered in the method.
The claims of copending Application 19/339,809 do not recite the fixed dose amounts (50mg to 900mg in instant independent claim 187) nor dosing times recited by the instant claims.
Gao teaches compositions containing crocetin for prevention and/or treatment of cancers and other conditions and diseases (abstract, claim 1) and a method of preventing, mitigating, or treating a disease or condition in a subject comprising administering an effective amount of the composition to a subject in need thereof (claim 11). Gao exemplifies the structure of alpha-crocetin, which is in the trans configuration (see paragraphs [0005]-[0006]). Gao teaches that compositions may be administered in the form of liposomes (paragraph [0104]) and that crocetin may be in a dose of about 50 mg to about 500 mg per dose (paragraph [0105]). Gao further teaches that in certain embodiments, more than one dose is administered (e.g., two or more doses spaced over time) (paragraph [0094]), and that the dose and dose frequency can vary according to the age, body weight, and conditions of an individual patient (paragraph [0105]). Gao further teaches that daily doses can be in single or divided doses (paragraph [0106]). Gao teaches that the method improves eye health, increases blood flow to the retina, and prevents ischemic retinopathy (claim 24, paragraph [0037]).
It would have been prima facie obvious to one of ordinary skill in the art to modify the method of administering liposomal trans-crocetin recited in copending Application No. 19/339,809 with the dose and dose frequency suggested by Gao, overlapping that of the instant claims. One of ordinary skill in the art would have been motivated to do so in order to optimize the dose and frequency to one that is suitable for treating ischemic conditions and which is suitable for the age, weight, and condition of the individual patient. It would further have been prima facie obvious to incorporate the liposomes into an aqueous solution, as suggested by Gao, in order to use a pharmaceutically acceptable solvent that can deliver the liposomal formulation by a desired route.
Given the subject matter of the instant claims is obvious and substantially overlaps the subject matter of copending Application No. 19/339,809, the instant claims are rejected on the ground of nonstatutory double patenting. This is a provisional nonstatutory double patenting rejection.
Claims 187-201 and 205-207 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-15, 21, 25, 34-37, and 39 of U.S. Patent No. US 12,458,597 B2 in view of Gao (US 2016/0199398 A1, published July 14, 2016, included on IDS submitted 01/21/2026).
The claims of copending U.S. Patent No. US 12,458,597 B2 are directed to a method of treating a disease or condition characterized by ischemia or hypoxia (see claims 21 and 25); thus, the method is interpreted as increasing the delivery of oxygen and that the subject is in need of increased oxygen delivery. Both the instant claims and those of U.S. Patent No. US 12,458,597 B2 recite administering a pegylated liposome encapsulating Q-trans-crocetin-Q, wherein Q is a multivalent cation counterion. The claims of U.S. Patent No. US 12,458,597 B2 further recite liposomes that have diameters, zeta potentials and trans-crocetin/lipid ratios in overlapping amounts, and the presence of a pharmaceutically acceptable carrier. While the copending claims do not teach that the liposomes are made by the method recited in instant claim 207, this is a product-by-process limitation that does not structurally limit the liposomes administered in the method.
The claims of U.S. Patent No. US 12,458,597 B2 do not recite the fixed dose amounts (50mg to 900mg in instant independent claim 187) nor dosing times recited by the instant claims. The claims of copending Application 19/333,941 do not explicitly recite that the liposomes are in an aqueous solution.
Gao teaches compositions containing crocetin for prevention and/or treatment of cancers and other conditions and diseases (abstract, claim 1) and a method of preventing, mitigating, or treating a disease or condition in a subject comprising administering an effective amount of the composition to a subject in need thereof (claim 11). Gao exemplifies the structure of alpha-crocetin, which is in the trans configuration (see paragraphs [0005]-[0006]). Gao teaches that compositions may be administered in the form of liposomes (paragraph [0104]) and that crocetin may be in a dose of about 50 mg to about 500 mg per dose (paragraph [0105]). Gao further teaches that in certain embodiments, more than one dose is administered (e.g., two or more doses spaced over time) (paragraph [0094]), and that the dose and dose frequency can vary according to the age, body weight, and conditions of an individual patient (paragraph [0105]). Gao further teaches that daily doses can be in single or divided doses (paragraph [0106]). Compositions for oral administration can be prepared in water or other aqueous vehicles (paragraph [0099], and compositions can comprise pharmaceutically acceptable sterile aqueous solution, dispersions, etc. (paragraphs [0100]). Gao teaches that the method improves eye health, increases blood flow to the retina, and prevents ischemic retinopathy (claim 24, paragraph [0037]).
It would have been prima facie obvious to one of ordinary skill in the art to modify the method of administering liposomal trans-crocetin recited in U.S. Patent No. US 12,458,597 B2 with the dose and dose frequency suggested by Gao, overlapping that of the instant claims. One of ordinary skill in the art would have been motivated to do so in order to optimize the dose and frequency to one that is suitable for treating ischemic conditions and which is suitable for the age, weight, and condition of the individual patient. It would further have been prima facie obvious to incorporate the liposomes into an aqueous solution, as suggested by Gao, in order to use a pharmaceutically acceptable solvent that can deliver the liposomal formulation by a desired route.
Given the subject matter of the instant claims is obvious and substantially overlaps the subject matter of U.S. Patent No. US 12,458,597 B2, the instant claims are rejected on the ground of nonstatutory double patenting.
Conclusion
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611