DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-5 and 9, drawn to a co-crystal of hydroxytyrosol and nicotinamide, wherein the co-crystal of hydroxytyrosol and nicotinamide has a molar ratio of hydroxytyrosol to nicotinamide of 1: 1; and a composition comprising the co-crystal of hydroxytyrosol and nicotinamide wherein the composition further comprises nicotinamide and/or a pharmaceutically acceptable excipient; and “the co-crystal of hydroxytyrosol and nicotinamide has an X-ray powder diffraction pattern showing characteristic peaks at least at 2θ angles of 11.4±0.2, 13.6±0.2, 14.9±0.2, 17.6±0.2, 18.8±0.2, 20.1±0.2, 20.3±0.2, and 20.8±0.2 degrees” as the species of the co-crystal of hydroxytyrosol and nicotinamide in the reply filed on March 16, 2026 is acknowledged.
The traversal is on the ground(s) that the claim amendment filed on March 16, 2026, which is filed after the mailing date of the Requirement for Restriction/Election mailed on February 5, 2026, incorporates the limitation of “wherein the co-crystal of hydroxytyrosol and nicotinamide has an X-ray powder diffraction pattern showing characteristic peaks at least at 2θ angles of 11.4±0.2, 13.6±0.2, 14.9±0.2, 17.6±0.2, 18.8±0.2, 20.1±0.2, 20.3±0.2, and 20.8±0.2 degrees" from original claim 3; and therefore, the claimed inventions share the same special technical feature and are linked by a single general inventive concept. Applicant further argues the cited prior art Xie et al. teaches a hydroxytyrosol nicotinate that contains a covalently bonded ester that is structurally distinct from the co-crystal instantly claimed. This is not found persuasive because the restriction requirement was made in light of the originally presented claims filed on September 5, 2023, which only positively recite “the co-crystal of hydroxytyrosol and nicotinamide has a molar ratio of 1:1” without any characteristics; therefore, the shared technical feature between the groups of inventions is combining hydroxytyrosol and nicotinamide (or closely related niacin/niacinamide) at a molar ratio of about 1:1, and not the solid state form. The XRPD-defined co-crystal is only in some claims (and added later), and therefore cannot rescue unity across all groups, especially method claims. The cited references are not relied upon to show that the prior art discloses the claimed co-crystal. Rather, they are relied upon to demonstrate that the alleged common feature linking the groups/species, i.e., the combination of hydroxyturosol with a niacin-derived compound at about 1:1 molar ratio for a therapeutic purpose that was already known. While Applicant argues that Xie et al. discloses a covalently bonded ester rather than co-crystal, this distinction is not dispositive for purpose of unity of invention. The analysis under PCT rule 13 focuses on whether the claimed groups share a common special technical feature that makes a contribution over the prior art, not whether the prior art is identical in form.
The requirement is still deemed proper and is therefore made FINAL.
Claims 6-8 and 11-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on March 16, 2026.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment filed on March 16,
2026, wherein claims 1, 3-4, 6 and 8-9 are amended; claims 2, 7 and 11-13 are unchanged; and claim 10 is cancelled.
Claims 1-9 and 11-13 are pending. Claims 6-8 and 11-13 are withdrawn.
Claims 1-5 and 9 are under examination in accordance with the elected invention and species.
Priority
The instant application 18/548,971 filed on September 5, 2023 is a 371 of PCT/CN2022/078935 filed on March 3, 2022, which claims priority to, and the benefits of Foreign Application No.
CN202110243777.0 filed on March 5, 2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/5/2023 and 8/1/2024 are is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Please note that foreign references without an English translation but have an English translation of the abstract will only have the abstract considered by the Examiner.
Drawings
The drawings are objected to because of the following informalities:
Fig. 6: the lines for each group are clustered together in the line graph, making it difficult to tell which line represents which group. For instance, it is not clear if the upper line indicated with the arrow (see Figure shown below) is supposed to represent Example 4 (
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) or other group?
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.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 9 is objected to because of the following informalities:
Regarding claim 9, the recitation of “[a] composition comprising the cocrystal of hydroxytyrosol and nicotinamide” is missing a comma between the term “composition” and “comprising”. Additionally, the term “comprises” is not being consistent throughout the claim, and should read –comprising—for the sake of consistency.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the composition of Example 4-5, does not reasonably provide enablement for the full scope of the composition comprising the co-crystal of hydroxytyrosol and nicotinamide, wherein the composition further comprises any amount of nicotinamide and/or a pharmaceutically acceptable excipient. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and, (8) the quantity of experimentation necessary. All of the Wands factors have been considered and discussed below:
(1, 5) The breadth of the claims and the Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the present case, instant claim 9 recites “[a] composition comprising the co-crystal of hydroxytyrosol and nicotinamide according to claim 1, wherein the composition further comprises nicotinamide and/or a pharmaceutically acceptable excipient”; and claim 1 is specifically drawn to “[a] co-crystal of hydroxytyrosol and nicotinamide, wherein the co-crystal of hydroxytyrosol and nicotinamide has a molar ratio of hydroxytyrosol to nicotinamide of 1:1, and wherein the co-crystal of hydroxytyrosol and nicotinamide has an X-ray powder diffraction pattern showing characteristic peaks at least at 2θ angles of 11.4±0.2, 13.6±0.2, 14.9±0.2, 17.6±0.2, 18.8±0.2, 20.1±0.2, 20.3±0.2, and 20.8±0.2 degrees”.
Therefore, the breadth of the claims covers a full genus of composition, comprising a co-crystal of hydroxytyrosol and nicotinamide that has a molar ratio of hydroxytyrosol to nicotinamide of 1:1 and the claimed X-ray powder diffraction pattern in combination with any amount of nicotinamide and/or any amount of any pharmaceutically acceptable excipient; and that encompass a broad API concentration ranges, multiple excipients classes and alternatives with broad concentration ranges, and numerous potential formulations.
(2, 3, 4) The state of the prior art, the level of skill in the art, and the predictability or lack
thereof in the art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the
art would have known, at the time the application was filed, about the subject matter to which the
claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art
refers to the skill of those in the art in relation to the subject matter to which the claimed invention
pertains at the time the application was filed.”
According to Tim (Journal of Chemical and Pharmaceutical Research, 2024, 16(5): 9-10), one skilled in the art would have known that polymorphs significantly affect solubility, dissolution rate, stability, and bioavailability; different polymorphs of the same compound can exhibit different pharmaceutical behavior, despite identical chemical composition (see e.g., p. 9, 1st paragraph). One skilled in the art would have also known that polymorphs forms are sensitive to formulation conditions, including excipients selection, processing conditions, and storage; Polymorphs may undergo phase transitions, recrystallization, and conversion to less stable forms during storage or manufacturing processes (see e.g., p. 9, 2nd paragraph and p. 10, 2nd paragraph). In other words, the crystal polymorph in the composition is highly sensitive to formulation variables. While the level of skilled in the art with respect to forming a composition would have been high, there is lack of predictability surrounding polymorph behavior in manufacturing the claimed genus of compositions.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation
of experimentation required:
In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the claimed invention. Although the instant specification provides two species of composition (Example 4 and Example 5) as depicted below (see page 10-11 of the specification):
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. In short, these compositions used a raw material composed of hydroxytyrosol and nicotinamide with a molar ratio of 1:2 and 1:3, respectively, to arrive at a composition containing the claimed co-crystal of hydroxytyrosol and nicotinamide in combination with “free nicotinamide”. It is respectfully noted that none of these compositions contain “a pharmaceutically acceptable excipient”. Additionally, it is further noted that the chemical stability of the co-crystal of hydroxytyrosol and nicotinamide, and the compositions obtained in Example 4-5 at 40°C/75% RH were compared in Example 7. As described therein, “the content of hydroxytyrosol was slightly decreased in the composition comprising the co-crystal of hydroxytyrosol and nicotinamide” after 30 days, which indicates the compositions slightly alter the chemical stability when compared to the co-cystal alone. Based on the limited disclosure provide, one skilled in the art could not reasonably predict which of the hundreds or thousands of pharmaceutically acceptable excipient encompassed by the claims can be incorporated without altering the polymorph behavior of the claimed co-crystal of hydroxytyrosol and nicotinamide. Additionally, one could not reasonably predict which amount of additional nicotinamide and/or pharmaceutically acceptable excipient can be added to the composition without changing the polymorphs forms. Therefore, the quantity of experimentation necessary to carry out the entire scope of the claimed invention is high, because it would require extensive formulation screening to determine stable and effective compositions. Given the sensitivity of polymorphic forms to formulation conditions and the lack of guidance in the specification, a person of ordinary skill in the art would be required to engage in undue experimentation to practice the full scope of the composition instantly claimed.
Accordingly, while the specification supports the composition of Example 4-5, the entire scope of composition instantly claimed is not enabled by the instant specification. To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Claims 1-5 and 9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To the extent that the recitation of “at least at 2θ angles” in claim 1 is referring to at least 2 or more of the 2θ angles positively recited, then the following 35 U.S.C. 112(a) rejection applies.
Instant claim 1 recites “[a] co-crystal of hydroxytyrosol and nicotinamide, wherein the co-crystal of hydroxytyrosol and nicotinamide has a molar ratio of hydroxytyrosol to nicotinamide of 1:1, and wherein the co-crystal of hydroxytyrosol and nicotinamide has an X-ray powder diffraction pattern showing characteristic peaks at least at 2θ angles of 11.4±0.2, 13.6±0.2, 14.9±0.2, 17.6±0.2, 18.8±0.2, 20.1±0.2, 20.3±0.2, and 20.8±0.2 degrees”.
In the present case, the instant specification only describes one species of co-crystal of hydroxytyrosol and nicotinamide with an X-ray powder diffraction pattern illustrated in Fig. 1; and the 2θ angles are described in the specification (see e.g., page 3) shown below:
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. To the extent that the claimed co-crystal of hydroxytyrosol and nicotinamide is referring to at least 2 or more characteristics peaks from the recited list in the X-ray powder diffraction pattern, it is insufficient to identify a specific crystalline species. A complete pattern containing at least four strongest reflections (major peaks) is often required to reveal the crystal's unique fingerprint. Weak reflections (minor peaks) cannot be used for crystalline phase or polymorphism identification, as they are often indistinguishable from background noise. Therefore, in order to sufficiently identify a specific co-crystal of hydroxytyrosol and nicotinamide, at least four major peak positions are required to determine arrangements of all atoms within its unit cell, including lattice parameters, crystal system, and space group.
In the absence of a sufficient recitation of a representative number of species for the claimed genus, while applicant is in possession of co-crystal of hydroxytyrosol and nicotinamide with an X-ray powder diffraction pattern as shown in Fig. 1, it is not apparent that Applicant was actually in possession of the full scope of the co-crystal of hydroxytyrosol and nicotinamide to the extent that the X-ray powder diffraction pattern contains less than four strongest peaks (reflections).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1-5 and 9 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.
Regarding claim 1, the recitation of “at least at 2θ angles” in the phrase “showing characteristics peaks at least at 2θ angles of 11.4±0.2, 13.6±0.2, 14.9±0.2, 17.6±0.2, 18.8±0.2, 20.1±0.2, 20.3±0.2, and 20.8±0.2 degrees” can leads to various interpretations. For instance, said recitation can be interpreted such that (i) at least all the 2θ angles are shown; or (ii) at least a certain amount of the 2θ angles are shown, e.g., at least 2 out of the eight 2θ angles are shown. If applicant is intending to the claim the first scenario, the recitation of “ at least at 2θ angles of” should read –at least at all 2θ angles of–. The lack of clarity renders the claim indefinite because one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Accordingly, claims 2-5 and 9 are rejected based on their dependency on a rejected base claim.
Regarding claim 5, the recitation of “at least at” in the phrase “wherein the co-crystal of hydroxytyrosol and nicotinamide has an infrared absorption spectrum showing absorption peaks at least at 3426 cm-1, 3371 cm-1, 3155 cm-1, 1692 cm-1…” can leads to various interpretations. For instance, said recitation can be interpreted such that (i) at least all the absorption peaks are shown; or (ii) at least a certain amount of the absorption peaks are shown, e.g., at least 2 out of 20 absorption peaks are shown. If applicant is intending to the claim the first scenario, the recitation of “at least at” should read –at least at all of the following positions:–. The lack of clarity renders the claim indefinite because one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim 3, the recitation of “substantially” in the phrase of “the co-crystal of hydroxytyrosol and nicotinamide has an X-ray powder diffraction pattern substantially as shown in FIG. 1” is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the degree of substantial and insubstantial. Therefore, when the term “substantially” is used in the context of X-ray powder diffraction pattern, it is not clear what is considered to be a substantial X-ray powder diffraction pattern (e.g., does all the peaks illustrated therein has to be present to be considered substantial?), and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim 4, 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, the claim recites the broad recitation the “co-crystal of hydroxytyrosol and nicotinamide has an onset melting temperature of 110±2 °C and a maximum peak of 111 ± 2 °C”, and the claim also recites “wherein the co-crystal of hydroxytyrosol and nicotinamide has a melting point of 111 °C ± 2 °C”, which is the narrower statement of the range/limitation. The differential scanning calorimetry characterized the compound by a melting range, which is the temperature interval between the onset temperature (first sign of liquid) and the clear point (full liquidity); as noted above, the claim recites the onset starting from a melting temperature of 110 ± 2 °C and has a maximum peak at 111 ±2 °C, which is a broader melting range; whereas the claim also recites a melting point of 111 °C ± 2 °C, which is just the maximum peak. The claim(s) 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.
Free of the Art
Claims 1-5 and 9 are free of the art.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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