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 .
Status of the Claims
Claims 1-12 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/CN2022/105559, filed on 07/13/2022.
Claim Objections
Claims 1, 5, 7, 9-10 and 12 are objected to because of the following informalities: The objected claims include numerous instances of elided words, as shown below:
Claim 1: “Ahas” should be “A has”;
Claim 5:
“Apreparation” should be “A preparation”;
“dissolvingHuperzine” should be “dissolving Huperzine”;
“standingat” should be “standing at”;
Claim 7: “toHuperzine” should be “to Huperzine”;
Claim 9:
“1),the” should be “1), the”;
“toHuperzine” should be “to Huperzine”;
Claim 10:
“Apreparation” should be “A preparation”;
“addingHuperzine” should be “adding Huperzine”;
Claim 12:
“solventto” should be “solvent to”;
“instep” should be “in step”.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities: The specification is littered with elided words, including a few examples shown below:
“HuperzineB”, which should be “Huperzine B” (page 1, line 5);
“Huperzine Aand itsadverse effectsare”, which should be “Huperzine A and its adverse effects are” (page 1, line 29);
“drug.However,” which should be “drug. However,” (page 2, line 3);
“HuperzineBcrystal”, which should be “Huperzine B crystal” (page 2, line 4.
The examples shown above are only a few select examples. Such errors are found throughout the instant Specifications.
Appropriate correction is required.
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.
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 1-12 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.
Claim 1 is drawn to a “crystal form A of Huperzine B, wherein the X-ray diffraction pattern of crystal form A has characteristic absorption peaks at the following 2q angular: 5 9.56±0.2, 13.90±0.2, 14.88±0.2, 16.00±0.2, 25.39±0.2 and 28.78±0.2.” A person of ordinary skill in the art would interpret claim 1 as indicating that there are multiple species that meet the limitation of being crystal Form A because the claim requires first that the composition is crystal Form A and then adds further limitations of analytical characterization that the composition must meet to satisfy the claim. Given that the Specification does not disclose multiple species as meeting the definition of crystal Form A, the claim is rendered ambiguous, and therefore indefinite. Claims 2-12 depend from claim 1 and do not resolve the indefiniteness of claim 1.
Claims 2-4 each further limit claim 1, each to a composition of matter that constitutes crystal Form A and each thereafter including additional analytical limitations, and are therefore indefinite because a person of ordinary skill in the art would interpret from the claim that there must be multiple crystalline polymorphs that qualify as “crystal Form A” if it is possible to be crystal Form A and not meet the further limitations.
Claim 10 further limits claim 1, itself drawn to a crystal form of huperzine B, to a method of preparing the crystal form of claim 1 comprises the following three steps:
adding huperzine B to a second solvent, heating and stirring and keeping for 48-96 hours to obtain a reaction mixture;
placing the reaction mixture in an open container and evaporating the solvent to dryness at room temperature;
drying in vacuum and collecting the resulting solid to obtain the crystal form.
Claim 10 is indefinite because the claim recites the limitation "second solvent" in “adding huperzine B to a second solvent”, and there is insufficient antecedent basis for this limitation in the claim: neither claim 1 nor claim 10 discloses a first solvent. The claim of a “second solvent” presupposes the existence of a first solvent, which is not present either in claim 10 or in its parent claim 1. A person of ordinary skill in the art would not understand when to introduce a first solvent into the method, or in what manner, capacity or role should be assigned to such a first solvent, and thus would not understand the metes and bounds of the method of claim 10.
Claims 11-12 depend from claim 10 and do not resolve the indefiniteness of claim 10 due to the lack of antecedence of the claim limitation “second solvent”.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “reaction mixture” in claim 10 is used by the claim to mean “solution,” while the accepted meaning is “a mixture in which a reaction occurs; a mixture of reactants.”1 The term is indefinite because the specification does not clearly redefine the term. The instant Specification includes the term “reaction mixture” 6 times, and in none of the instances does any chemical reaction occur (pages 4, 6 and 10-11). A person of ordinary skill in the art would expect claim 10 to include at least one reactant and at least one product to be included in any method that includes a “reaction mixture”; however, the method of claim 10 includes only huperzine B and a “second solvent”. If the method of claim 10 is directed toward obtaining huperzine B, then huperzine B must be the product, and therefore the method lacks a reactant. Alternatively, since the method requires a person of ordinary skill in the art to begin with huperzine B and add it to a “reaction mixture”, it would appear that a produce that is not huperzine B is expected, and is missing from the method of claim 10. Thus, a person of ordinary skill in the art would not understand the metes and bounds of the method of claim 10 in regard to what reactant or product is missing from the claimed method given that a reaction mixture is present in the method but no chemical reaction is apparent from the steps of the claim that are to be performed.
Claims 11-12 depend from claim 10 and do not resolve the indefiniteness of claim 10 due to the indefiniteness of the term “reaction mixture” which appears to be used to mean “solution”.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4 are unpatentable over Zhao.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao (CN 102070527 A).
Claim 1 is drawn to a crystal form A of Huperzine B, characterized by specific X-ray diffraction pattern peaks. According to the instant disclosure, this crystal form A can be obtained by heating a solution of huperzine B in ethanol and allowing the solution to cool, thereupon obtaining crystalline huperzine B (Examples 1 and 3, page 9, lines 15-22, and page 10, lines 10-17, respectively, of the instant Specification).
Claims 2-3 further limit claim 1 to wherein the crystal form exhibits additional X-ray diffraction peaks.
Claim 4 further limits claim 1 to wherein the crystal form exhibits specific Raman spectroscopy peaks.
Zhao discloses a method of extracting and purifying the compounds huperzine A and huperzine B from the plant known as Phlegmariurus phlegmaria (L) Holub (Abstract). Zhao’s process includes the crystallization of huperzine B, wherein the extracted huperzine B is diluted into 80% ethanol in a volume ratio of 100-150x, heated and treated with decolorizing charcoal, filtered while hot, concentrated to 1/15th the prior volume and allowed to stand for 8 hours, and then filtered to obtain “coarse” crystals. The crystals thereby obtained are then dissolved into 95% ethanol in a volume ratio of 100-150x, heated to dissolve the huperzine B, then concentrated to 1/15th the prior volume, left to stand to crystallize, and filtered to obtain white needle-shaped crystals (paragraphs [0015]-[0016]). While Zhao does not report X-ray diffraction attributes or Raman spectroscopy behavior of the crystalline huperzine B thereby obtained, a person of ordinary skill in the art would have a reasonable expectation of success in arriving at the claimed polymorph described as “crystal Form A" in the instant application by using the method of Zhao, because Zhao’s method matches to the multiple instant Examples 1-3 in obtaining a crystal form of huperzine B from the cooling of a hot ethanolic solution, and a person of ordinary skill in the art would at once recognize that X-ray diffraction peaks and Raman spectroscopic behavior are inherent attributes of a composition of matter, for example a crystal polymorph. Applicant is directed to MPEP 2113.II:
"The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an nonobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 799, 803, 218 USPQ 289, 292-33 (Fed. Cir. 1983).
Applicant’s invention is unpatentable over the disclosure of Zhao, because the claimed crystal Form A is obtained by the same method as that of Zhao of dissolving huperzine B in a hot ethanolic solution and allowing the solution to cool to obtain the crystalline solid, and because a person of ordinary skill in the art would at once recognize that that X-ray diffraction peaks and Raman spectroscopy behavior are inherent attributes of a composition of matter.
Thus, the invention was prima facie obvious at the time of filing.
Claims 1-4 are unpatentable over Li.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Li (CN 102432535 A).
The limitations of claims 1-4 are discussed in the rejection above and hereby incorporated into the instant rejection.
Li discloses a method of extracting and purifying the compounds huperzine A and huperzine B from the plant known alternately as Melaleuca pagoda or Huperzia serrata (Abstract). Li’s process includes the crystallization of huperzine B, wherein huperzine B isolated by chromatographic separation is dissolved in 85-95% ethanol in a volume ratio of 100-150x, heated and concentrated to a volume ratio of 10-12x and allowed to stand for white needle-like crystals to precipitate, and then filtered to huperzine B crystals (paragraph [0014], within section “Summary of the Invention”, step 8). Li further provides 3 Examples, and within each example, the process is carried out as described above, with a final step of vacuum drying the crystals prior to weighing for yield (final paragraph of each Example: paragraphs [0024], [0029] and [0033]). While Li does not report X-ray diffraction attributes or Raman spectroscopy behavior of the crystalline huperzine B thereby obtained, a person of ordinary skill in the art would have a reasonable expectation of success in arriving at the claimed polymorph described as “crystal Form A" in the instant application by using the method of Li, because Li’s method matches to the multiple instant Examples 1-3 of the instant Specification in obtaining a crystal form of huperzine B from the cooling of a hot ethanolic solution (Examples 1 and 3, page 9, lines 15-22, and page 10, lines 10-17, respectively, of the instant Specification), and a person of ordinary skill in the art would at once recognize that X-ray diffraction peaks and Raman spectroscopic behavior are inherent attributes of a composition of matter, for example a crystal polymorph. Applicant is directed to MPEP 2113.II:
"The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an nonobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 799, 803, 218 USPQ 289, 292-33 (Fed. Cir. 1983).
Applicant’s invention is unpatentable over the disclosure of Li, because the claimed crystal Form A is obtained by the same method as that of Li of dissolving huperzine B in a hot ethanolic solution and allowing the solution to cool to obtain the crystalline solid, and because a person of ordinary skill in the art would at once recognize that that X-ray diffraction peaks and Raman spectroscopy behavior are inherent attributes of a composition of matter, including a crystal polymorph.
Thus, the invention was prima facie obvious at the time of filing.
Claim 5 further limits claim 1 to a method of preparing the crystal form of claim 1, comprising the following steps:
dissolving huperzine B in a first solvent under the heating conditions to obtain a first solution of huperzine B;
performing step 2a) or step 2b):
cooling down the first solution of huperzine B and slowly evaporating the solvent to dryness;
cooling down to room temperature to precipitate crystals and standing at about 0°C;
drying the product obtained in step 2) in vacuum and collecting the resulting solid to obtain the crystal form.
The method of Li to obtain crystalline huperzine B differs from the method of instant claim 5 in that Li does not keep the precipitated crystals sitting in the mother liquor at 0°C prior to filtering them to obtain the crystal product. However, a person of ordinary skill in the art would have a reasonable expectation of success in modifying the method of Li to include a step of cooling the product to 0°C before filtering the crystals and vacuum drying them, because the crystals having already formed prior to the cooling could not be affected by this superfluous additional step. Claim 5 does not require that no steps occur between the claimed step 2) and step 3), and therefore does not require that the mother liquor is removed by evaporation if step 2b) is selected for step 2).
Claims 6-7 further limit claim 5 to additional requirements for when step 2a) is selected as the action of step 2), but do not require that step 2a) is selected for the action of step 2a), and are therefore fulfilled by the modified method of Li that includes a cooling step discussed above.
Claim 8 further limits claim 5 to wherein the “first solvent” is selected from a Markush group that includes ethanol when step 2b) is selected as the action of step 2). As discussed above, Li uses ethanol for the recrystallization of huperzine B.
Claim 9 further limits claim 5 to wherein, if step 2b) is selected as the action for step 2), then the conditions of step 1) are further limited to wherein the ratio of solvent to huperzine B (mg solid/mL solvent) is in the range of 15-90, or the heating temperature is 70-90°C. A person of ordinary skill in the art would at once recognize that the method of Li, which uses 85% ethanol, would boil at the well-known boiling point of the ethanol/water azeotrope that is 97% ethanol, and boils at 78.15°C.2 Thus, the method of Li, modified as discussed above to include a cooling step after crystal formation, meets the limitations of claim 9.
Applicant’s invention is unpatentable over the disclosure of Li, because a person of ordinary skill in the art would have a reasonable expectation of success in modifying the method of Li to include a step of cooling the ethanolic mother liquor containing the precipitated crystals, prior to filtering and vacuum-drying the obtained crystals, because this step does not alter the outcome of the method of recrystallizing huperzine B.
Thus, the invention was prima facie obvious at the time of filing.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 See, for example, the Oxford English Dictionary online: https://www.oed.com/dictionary/reaction-mixture_n?tl=true
2 See for Example, Jacques, K.A., et al.; The Alcohol Textbook, 4th Edition, page 402 (Glossary (The Alcohol Alphabet”), definition: “azeotrope”), Nottingham University Press, Nottingham, U.K.; 2003)
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