Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 11, 2025 has been entered.
DETAILED ACTION
3. Claims 37, 39 – 44, 46 – 47, 49 – 57, and 59 – 63 are pending in this application. Applicant’s Amendment and Remarks, filed November 11, 2025, is entered, wherein claims 37, 41 – 43, 47, 50, and 60 are amended, claims 61 – 63 are new, claims 51 – 55 and 59 are withdrawn, and claims 1 – 36, 38, 45, 48, and 58 are canceled.
Priority
This application is a national stage application of PCT/NL2020/050191, filed March 20, 2020, which claims benefit of foreign priority document NL2022788, filed March 22, 2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Objections
5. The objection of claim 47 in the previous Office Action, mailed July 23, 2025, is withdrawn in view of the amended claim 47.
Withdrawn Rejections
6. The rejection of claims 37, 39 – 46, and 56 in the previous Office Action, mailed July 23, 2025, under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a condition, such as diabetes mellitus type 2, does not reasonably provide enablement for preventing any condition, such as diabetes mellitus type 2, has been considered and is withdrawn in view of the amended claim 37.
The rejection of claims 37, 39 – 44, 47, 49, and 60 in the previous Office Action, mailed July 23, 2025, under 35 U.S.C. 102(a)(1) as being anticipated by Mathew has been considered and is withdrawn in view of the amended claim 37.
The rejection of claims 37, 39 – 47, 49, 56, and 60 in the previous Office Action, mailed July 23, 2025, under 35 U.S.C. 103 as being unpatentable over Mathew in view of Sumiyoshi has been considered and is withdrawn in view of the amended claim 37.
The rejection of claims 47, 49 – 50, 57 – 58, and 60 in the previous Office Action, mailed July 23, 2025, under 35 U.S.C. 103 as being unpatentable over Schoenfisch et al. in view of Andersen et al. has been considered and is withdrawn in view of the amended claim 47.
Claim Objections
Claims 43 and 59 – 61 are objected to because of the following informalities:
Claim 43, line 1, “and” should be inserted immediately after “mammal”.
Claim 59, line 1, recites the status identifier as “Previously presented”, which should be replaced with “Withdrawn”.
Claim 60, line 2, “of” should be inserted immediately after “conversion”.
Claim 61, line 1, “a condition” should read “the condition”.
Claim 61, line 2, “chitosan nitrate into nitrate” should read “chitosan nitrate into nitrite”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 46 and 63 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
a. Claim 46 recites “The method according to claim 45” in line 1. However, the claim set filed November 11, 2025, indicates that claim 45 has been canceled. As claim 46 is dependent upon a canceled claim, it renders the dependency unclear. For compact prosecution, claim 46 is interpreted as “The method according to claim 37”.
b. Claim 63 recites the limitation “the composition” in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 63 depends from claim 47 and recites “the composition”, however, claim 47 never recites “composition. It is unclear which composition the claim is referring to.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
Claims 37, 39 – 44, 46, 56, and 61 – 62 are rejected under 35 U.S.C. 103 as being unpatentable over Francois (EP0755253B1) in view of Omar et al. (Nitric Oxide, 2012, Vol. 26, Issue 4, page 229 – 240, Reference included with PTO-892), Hecht (Healthline, 2018, Reference included with PTO-892), and Lárez Velásquez et al. (E-Polymer, 2008, Vol. 8, Issue 1, Reference included with PTO-892).
Regarding claims 37, 39 – 44, 46, 56, and 61 – 62, Francois teaches a composition comprising an antimigraine compound and chitosan, which may be formulated as intranasal administration (para. [0001]). The composition may comprise the pharmaceutically acceptable salt form of chitosan (para. [0010]), wherein the salt form may be chitosan nitrate (para. [0013]). The composition can be administered via the nasal route using a nasal spray device (para. [0031]). The composition has been tested on healthy volunteers (para. [0037]).
However, Francois does not teach that the chitosan nitrate has a molecular weight in the range of 20 – 500 kDa and acts as an NO donor for treating a condition related to NO deficiency in a subject, wherein the condition is disorders related to the airways, and/or the subject is in need of pain treatment. Francois does not teach the composition may treat arterial pulmonary hypertension and post traumatic pain and/or swelling. Francois does not teach that the weight ratio between nitrate anion and chitosan is between 1:1 and 1:10. Francois does not teach that the treatment of the condition related to NO deficiency is due to conversion of chitosan nitrate into nitrite by anaerobic bacteria present in mucous membranes of the subject, and further conversion of the nitrate into NO.
Omar et al. teach that inorganic nitrates/nitrites mediate the principal effects via nitric oxide. Inorganic nitrate has simple ionic structures. Orally ingested inorganic nitrate can utilize the enterosalivary circulation, which may prevent an abrupt effect or toxic levels of nitrite and can prolong NO-related effects. In addition, inorganic nitrate/nitrite may compensate for diminished endothelial function, and tolerance has not been reported. Omar et al. also disclose that inorganic nitrate/nitrite has also been reported to have important cytoprotective effects (Abstract). The use of inorganic nitrate and nitrite continues until the early part of the 20th century for cardiovascular disease and also other conditions, such as epilepsy, lung diseases and as diuretics to treat oedema (page 230, Left Col., para. 1). Omar et al. disclose that inorganic nitrate and nitrite are hydrophilic salts which do not undergo first pass metabolism by the liver and so can be readily administered orally. Ingestion of nitrate by humans results in its reduction to nitrite via the enterosalivary circulation (page 230, Left Col., para. 4). Upon secretion into the oral cavity, the nitrate in the saliva is reduced to nitrite by the action of commensal bacteria found on the back of the tongue. The swallowed nitrite, under the influence of the acidic conditions in the stomach, becomes protonated to nitrous acid. A proportion of the nitrous acid decomposes to produce NO (page 230, Right Col., para. 4; page 231, Left Col., para. 1). In a rat model of hypertension, intervention with high dose nitrate results in a reduction in blood pressure (page 236, Left Col., para. 3). The use of inorganic nitrite in human studies results in vasodilatation in the pulmonary vasculature leading to reduction in pulmonary arterial pressure (PAP) (page 236, Right Col., para. 1).
Hecht teaches that oedema has a wide variety of causes (page 2, para. 3). One of the common causes is injury, wherein a fraction, sprain, strain, or bad bruise in leg, ankle, foot or hand can result in swelling and pain (page 2, para. 5).
Lárez Velásquez et al. teach the synthesis of chitosan nitrate salt by preparing an aqueous medium of biopolymer chitosan and employing an excess of HNO3 (Abstract). The chitosan used has a molecular weight of 400,000 Da and acetylation degree of 0.162. The chitosan salt is prepared by placing 3.0 g of chitosan in 125 mL deionized water and a small stoichiometric excess of HNO3 (65%) is added (page 6, para. 4; page 7, para. 1). Lárez Velásquez et al. teach that chitosan has demonstrated to be a promising material for biomedical applications, such as controlled drug release (page 1, para. 1). Furthermore, Lárez Velásquez et al. disclose that charged moieties on the polymer chains originate from diverse conformational arrangements which contribute to the modeling of chitosan polyelectrolyte behavior and conformational arrangements of polyelectrolyte chains in aqueous solution are controlled by different factors, such as molecular weight (page 1, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to administer a pharmaceutical composition comprising chitosan nitrate as taught by Francois to treat a condition related to NO deficiency, which includes conditions related to airways, pain, or a metabolic disorders in view of Omar et al. because Omar et al. teach that inorganic nitrate would generate NO and demonstrate that inorganic nitrate, as a source of NO, is useful in treating cardiovascular disease, lung diseases, and oedema. One would have been motivated to utilize the nitrate salt form of chitosan to provide inorganic nitrate as an NO donor because it is known in the art that inorganic nitrate is able to convert to NO inside body and to treat the NO-deficiency conditions and Francois teach that chitosan nitrate has been used in treatment and it is safe to use in human. Claims 43 and 44 recite the limitations “the subject…is in need of pain treatment” and “the condition is…post traumatic pain and/or swelling”. Omar et al. teach that inorganic nitrate may be used to treat oedema and Hecht teaches that oedema may be caused by injury and is associated with pain. Injury is a form of trauma. Oedema occurs after injury is post-traumatic. The disclosure of Omar et al. and Hecht read on the limitations of claims 43 – 44. Lárez Velásquez et al. teach that chitosan polyelectrolyte conformation are controlled by factors, such as molecular weight. For the molecular weight of chitosan, one would have performed routine experimentation to discover the best molecular weight for the optimal treatment characteristics and desired formulation characteristics. Claims 56 recites the limitation “the weight ratio between nitrate anion and chitosan is between 1:1 and 1:10”. Lárez Velásquez et al. teach the preparation of chitosan nitrate by reacting 3.0 g of chitosan with a small stoichiometric excess of HNO3. The chitosan has an acetylation degree of 0.162, which indicates that approximately 0.838 fraction of chitosan are deacetylated and thus providing amine groups capable of protonation and counterion pairing with nitrate anion. The excess of HNO3 also indicates the acid is present in an amount sufficient to protonate the available amine groups for counterion pairing with nitrate. Based on this information, the weight ratio of nitrate anion and chitosan is calculated to be 1:3.2, which reads on the limitation of claim 56. One of the ordinary skill in the art would have had a reasonable expectation of success to administer a pharmaceutical composition comprising chitosan nitrate as taught by Francois to treat a condition related to NO deficiency, which includes conditions related to airways, pain, or a metabolic disorders in view of Omar et al. because Francois teaches that the nitrate salt form of chitosan and Omar et al. teach that inorganic nitrate, as an NO donor, is converted to NO in body and is used to treat the NO-deficiency conditions.
Claims 47, 49 – 50, 57, 60, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Francois (EP0755253B1) in view of Omar et al. (Nitric Oxide, 2012, Vol. 26, Issue 4, page 229 – 240, Reference included with PTO-892), Adler (Future Science, 2015, Vol. 1, Issue 1, Reference included with PTO-892), Torregrossa et al. (Journal of Geriatric Cardiology, 2011, Vol. 8, Issue 4, page 230 – 242, Reference included with PTO-892), and Lárez Velásquez et al. (E-Polymer, 2008, Vol. 8, Issue 1, Reference included with PTO-892).
Regarding claims 47, 49 – 50, 57, 60, and 63, Francois teaches a composition comprising an antimigraine compound and chitosan, which may be formulated as intranasal administration (para. [0001]). The composition may comprise the pharmaceutically acceptable salt form of chitosan (para. [0010]), wherein the salt form may be chitosan nitrate (para. [0013]). The composition can be administered via the nasal route using a nasal spray device (para. [0031]). The composition has been tested on healthy volunteers (para. [0037]).
However, Francois does not teach that the chitosan nitrate has a molecular weight in the range of 20 – 500 kDa and acts as an NO donor. Francois does note teach using chitosan nitrate for skin protection and/or for promoting healthy aging, wherein the skin protection is a protection against environmental influences or reduction of skin aging, and the subject suffers from a lack of nitric oxide, wherein the lack of nitric oxide is due to aging. Francois does not teach that the weight ratio between nitrate anion and chitosan is between 1:1 and 1:10. Francois does not teach that the skin protection and/or promotion of healthy aging is due to conversion of chitosan nitrate into nitrite by anaerobic bacteria present in mucous membranes of the subject, and further conversion of the nitrate into NO.
Omar et al. teach that inorganic nitrates/nitrites mediate the principal effects via nitric oxide. Inorganic nitrate has simple ionic structures. Orally ingested inorganic nitrate can utilize the enterosalivary circulation, which may prevent an abrupt effect or toxic levels of nitrite and can prolong NO-related effects. In addition, inorganic nitrate/nitrite may compensate for diminished endothelial function, and tolerance has not been reported. Omar et al. also disclose that inorganic nitrate/nitrite has also been reported to have important cytoprotective effects (Abstract). Omar et al. disclose that inorganic nitrate and nitrite are hydrophilic salts which do not undergo first pass metabolism by the liver and so can be readily administered orally. Ingestion of nitrate by humans results in its reduction to nitrite via the enterosalivary circulation (page 230, Left Col., para. 4). Upon secretion into the oral cavity, the nitrate in the saliva is reduced to nitrite by the action of commensal bacteria found on the back of the tongue. The swallowed nitrite, under the influence of the acidic conditions in the stomach, becomes protonated to nitrous acid. A proportion of the nitrous acid decomposes to produce NO (page 230, Right Col., para. 4; page 231, Left Col., para. 1).
Adler teaches that the role of NO in skin’s response to UV radiation and skin pigmentation has paved a way for future use of NO as a cosmeceutical and/or novel non-UV tanning agent capable of reducing photoaging (page 12, Executive summary).
Torregrossa et al. teach that constitutive production of NO is reduced with aging (Abstract).
Lárez Velásquez et al. teach the synthesis of chitosan nitrate salt by preparing an aqueous medium of biopolymer chitosan and employing an excess of HNO3 (Abstract). The chitosan used has a molecular weight of 400,000 Da and acetylation degree of 0.162. The chitosan salt is prepared by placing 3.0 g of chitosan in 125 mL deionized water and a small stoichiometric excess of HNO3 (65%) is added (page 6, para. 4; page 7, para. 1). Lárez Velásquez et al. teach that chitosan has demonstrated to be a promising material for biomedical applications, such as controlled drug release (page 1, para. 1). Furthermore, Lárez Velásquez et al. disclose that charged moieties on the polymer chains originate from diverse conformational arrangements which contribute to the modeling of chitosan polyelectrolyte behavior and conformational arrangements of polyelectrolyte chains in aqueous solution are controlled by different factors, such as molecular weight (page 1, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to administer a pharmaceutical composition comprising chitosan nitrate as taught by Francois as an NO donor to a subject suffers from a lack of nitric oxide due to aging for protection of skin against UV radiation in view of Omar et al., Adler, and Torregrossa et al. because Francois teaches a pharmaceutical composition comprising chitosan nitrate, Omar et al. teach that inorganic nitrate mediates the principal effects via nitric oxide, including nitrate to NO conversion, Adler teaches that NO is capable of reducing photoaging caused by UV radiation, and Torregrossa et al. teach that the NO production is reduced with age. One would have been motivated to administer a pharmaceutical composition comprising chitosan nitrate as taught by Francois as an NO donor to a subject suffers from a lack of nitric oxide due to aging for protection of skin against UV radiation in view of Omar et al., Adler, and Torregrossa et al. because Omar et al. teach that inorganic nitrate is a source of NO and Adler teaches that NO will protect skin from photoaging. According to Torregrossa et al., it is obvious for one of ordinary skill in the art to administer said composition to treat a subject that is suffering from a lack of nitric oxide caused by aging because Torregrossa et al. disclose that NO production will be reduced when aged. Claims 57 recites the limitation “the weight ratio between nitrate anion and chitosan is between 1:1 and 1:10”. Lárez Velásquez et al. teach the preparation of chitosan nitrate by reacting 3.0 g of chitosan with a small stoichiometric excess of HNO3. The chitosan has an acetylation degree of 0.162, which indicates that approximately 0.838 fraction of chitosan are deacetylated and thus providing amine groups capable of protonation and counterion pairing with nitrate anion. The excess of HNO3 also indicates the acid is present in an amount sufficient to protonate the available amine groups for counterion pairing with nitrate. Based on this information, the weight ratio of nitrate anion and chitosan is calculated to be 1:3.2, which reads on the limitation of claim 57. For the molecular weight of chitosan, Lárez Velásquez et al. teach that chitosan polyelectrolyte conformation are controlled by factors, such as molecular weight. One would have performed routine experimentation to discover the best molecular weight for the optimal treatment characteristics and desired formulation characteristics. One of the ordinary skill in the art would have had a reasonable expectation of success to administer a pharmaceutical composition comprising chitosan nitrate as taught by Francois as an NO donor to a subject suffers from a lack of nitric oxide due to aging for protection of skin against UV radiation in view of Omar et al., Adler, and Torregrossa et al. because Francois teaches the composition comprising chitosan nitrate, which is an inorganic nitrate, Omar et al. teach that inorganic nitrate is an NO donor to treat various conditions, Adler teaches that NO may be used as a skin protection against UV radiation, and Torregrossa et al. disclose that production of NO is reduced with age, thereby, providing a reason for targeting geriatric population.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed November 11, 2025, have been fully considered and are found to be not persuasive.
Regarding Mathew, Applicant argues that Matthew is silent on the use of chitosan nitrate as NO donor. Regarding Schoenfisch et al., Applicant argues that Schoenfisch et al. do not disclose chitosan nitrate or its use as an NO donor.
Regarding Sumiyoshi, Applicant argues that Sumiyoshi teaches the effects of chitosan itself, not chitosan nitrate and a skilled artisan would not consider using the chitosans of Sumiyoshi in a method that relies on the NO donor capacity of chitosan nitrate.
Regarding Andersen et al., Applicant argues that Andersen et al. teach the effects of chitosan itself, not chitosan nitrate and provides no teaching or suggestion that chitosan nitrate would be suitable as NO donor.
Finally, Applicant argues that inherent features cannot be attributed to a hypothetical composition that is not disclosed as such in the cited prior art documents.
These arguments are moot because the new rejections are no longer relying on the previously cited references. The combination of Francois, Omar et al., Adler, Torregrossa et al., and Lárez Velásquez et al. reads on the limitations of the claims because Francois teaches a pharmaceutical composition comprising chitosan nitrate, Omar et al. teach that inorganic nitrate is an NO donor that is capable of treating various diseases, Adler teaches that NO may protect skin from UV radiation, and Torregrossa et al. teach that aging will reduce the production of NO. One would have a reasonable expectation of success to administer the composition comprising chitosan nitrate as taught by Francois to treat NO-deficiency conditions because Omar et al. teach that inorganic nitrate is a NO donor that may treat the claimed conditions and Adler teaches that NO provide protection for skin against UV radiation.
Regarding the unexpected results, Applicant demonstrates that the chitosan nitrate with the claimed molecular weight of chitosan exhibits lower nitrate excretion via urine compared to potassium nitrate. However, there is no comparison to show outside of the claimed range to support the unexpected results for the molecular weight claimed. As set forth in MPEP § 716.02 (d) (II), to establish unexpected results over a claimed range, Applicant 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). Based on the data provided now, the examiner will not be able to determine the unexpected results.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693