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 .
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 14–16 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jackson et al.
Claim 14
Claim 14 recites a crystalline form of calcium D-glycerate of formula (II) characterized, using XRPD, by diffraction peaks at 15.4°±0.2°, 17.0°±0.2°, and 27.1°±0.2° 2θ. The claim limitations are confirmed at claim 14 of the published application.
Jackson expressly discloses the same calcium D-glycerate hydrate species. Specifically, Jackson teaches concentrating a calcium-neutralized D-glycerate solution until the calcium D-glycerate crystallizes, followed by two recrystallizations from water and drying in air. Jackson expressly identifies the isolated crystalline product as calcium D-glycerate dihydrate having a melting point of 141–142 °C. Jackson independently repeats the preparation, employs three recrystallizations from water, and again obtains calcium D-glycerate dihydrate having the same 141–142 °C melting point. Jackson, p. 1002, right-hand column, calcium D-glycerate preparation paragraphs.
Jackson further analytically confirms the hydrate stoichiometry rather than merely assigning the material a nominal “dihydrate” designation. For C₆H₁₀O₈Ca·2H₂O, Jackson calculates 12.59% water and reports measured water values of 12.78% and 12.61% for material obtained through two separate routes. Jackson, p. 1002, “Anal.” paragraph immediately following the second calcium D-glycerate preparation.
The specification identifies crystalline Form II as calcium D-glycerate having two molecules of water of crystallization. Specification ¶¶ [0049]–[0053]. In particular, ¶ [0050] identifies the Form-II peaks at 15.4°, 17.0°, and 27.1°; ¶ [0051] identifies the additional claim-15 peaks; ¶ [0052] identifies the additional claim-16 peaks; and ¶ [0053] states that Form II loses its water of crystallization at 125–150 °C and that the measured water loss corresponds to two molecules of water of crystallization. The corresponding disclosure is reproduced in the published application.
Thus, Jackson does not merely disclose calcium glycerate generally. Jackson discloses and physically isolates a crystalline material having the same D stereochemistry, the same calcium glycerate salt identity, the same two-water hydrate stoichiometry, and reproducible thermal behavior. Jackson's repeated preparation and quantitative water analysis provide a sound factual basis for determining that the crystalline calcium D-glycerate dihydrate obtained by Jackson is identical or substantially identical to the calcium D-glycerate dihydrate recited in claim 14.
The fact that Jackson did not characterize its 1937 crystals by Cu-Kα XRPD does not, by itself, distinguish the claimed product. An XRPD peak position is a physical characteristic resulting from the periodic crystal lattice of the crystalline material. Where the prior-art crystalline product is the same crystalline product, subsequently measuring its diffraction pattern does not create a new composition merely because that characteristic had not previously been appreciated. See MPEP § 2112, explaining that discovery or characterization of a previously unappreciated property of an old composition does not make the old composition patentably new.
Accordingly, because Jackson's crystalline calcium D-glycerate dihydrate appears to be the same crystalline dihydrate recited by claim 14, the XRPD peaks at 15.4°±0.2°, 17.0°±0.2°, and 27.1°±0.2° are considered inherent physical characteristics of Jackson's crystalline material.
Claim 14 is therefore prima facie anticipated by Jackson.
Claim 15
Claim 15 depends from claim 14 and further requires XRPD diffraction peaks at 23.8°±0.2°, 28.6°±0.2°, and 32.0°±0.2°. Claim 15 and these additional peak limitations are expressly set forth in the published claims.
As discussed with respect to claim 14, Jackson expressly produces crystalline calcium D-glycerate dihydrate and analytically confirms the two-water stoichiometry. Jackson, p. 1002, calcium D-glycerate preparation and analytical paragraphs.
The present specification identifies the additional 23.8°, 28.6°, and 32.0° peaks as further diffraction peaks of the same crystalline Form II, rather than as ingredients, treatments, or compositional limitations different from the Form-II material of claim 14. Specification ¶ [0051].
Accordingly, for the reasons stated for claim 14, these additional diffraction peaks constitute further inherent diffraction characteristics of the same crystalline calcium D-glycerate dihydrate. No separate component or structural constituent is added by claim 15.
Claim 15 is therefore prima facie anticipated by Jackson.
Claim 16
Claim 16 depends directly from claim 14 and further requires XRPD diffraction peaks at 12.9°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 21.2°±0.2°, 22.3°±0.2°, 36.4°±0.2°, 37.6°±0.2°, and 39.5°±0.2°.
The specification identifies these values as additional peaks of the same crystalline Form II described in claim 14. Specification ¶ [0052].
Jackson's disclosure remains directed to the same isolated crystalline calcium D-glycerate dihydrate discussed above, including two independent preparations producing the same 141–142 °C material and quantitative analytical confirmation of the dihydrate. Jackson, p. 1002.
Therefore, based on the same identity and inherency analysis applied to claim 14, the additional claim-16 diffraction peaks are considered inherent physical characteristics of Jackson's crystalline calcium D-glycerate dihydrate.
Claim 16 is therefore prima facie anticipated by Jackson.
Examiner's inherency finding
The inherency finding is based collectively on the following objective facts:
Jackson expressly identifies the stereoisomer as D-glycerate, not DL-glycerate.
Jackson expressly identifies the isolated material as a crystalline calcium D-glycerate dihydrate.
Jackson obtains the crystalline dihydrate independently by two preparations and repeated water recrystallization.
Both preparations exhibit the same 141–142 °C thermal behavior.
Jackson's measured water values of 12.78% and 12.61% closely correspond to the calculated 12.59% for two waters per calcium D-glycerate formula unit.
The instant Form II is likewise a calcium D-glycerate having two molecules of water of crystallization, specification ¶ [0053].
Precritical U.S. patent and technical literature independently establishes continued use and commercial availability of calcium D-glycerate dihydrate, including 99%-purity commercial material.
These facts provide considerably more than a statement that the claimed XRPD peaks “might” occur. They provide the factual and technical basis required by MPEP § 2112 for the prima facie determination that the prior-art and claimed crystalline dihydrate are the same material.
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.
Claims 14–16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jackson et al. in view of US Patent Publication Number 2002/0137754, Sato et al., and US Patent Publication Number 2017/0263945
Jackson expressly provides crystalline calcium D-glycerate dihydrate having quantitatively confirmed dihydrate stoichiometry and reproducible 141–142 °C thermal behavior. Jackson, p. 1002.
Jackson does not expressly report an XRPD pattern. This difference does not, on the present record, establish a different product. Rather, claims 14–16 characterize the known crystalline D-dihydrate by physical diffraction properties.
The conclusion that calcium D-glycerate dihydrate itself was well established before the critical date is independently corroborated by:
U.S. 2002/0137754, Example 17, ¶¶ [0187]–[0188], which expressly employs D-glyceric acid calcium salt dihydrate;
Sato et al. (2014), experimental section, which expressly identifies calcium D-glycerate dihydrate obtained commercially from Sigma-Aldrich≈.
U.S. 2017/0263945, Example 6, ¶ [0286], which expressly identifies 99% D-glyceric acid calcium salt dihydrate obtained from Sigma-Aldrich≈ and used as received.
Moreover, Taga had already demonstrated X-ray crystal-structure determination of calcium glycerate dihydrate. Taga, p. 1697, Abstract, identifies a defined calcium DL-glycerate dihydrate crystal lattice and reports its crystallographic unit-cell parameters and two lattice water molecules.
Thus, to the extent that claims 14–16 are considered to differ from Jackson only by expressly stating an XRPD characterization of the previously known crystalline D-dihydrate, characterizing that old crystalline material by X-ray diffraction would not render the old material patentably new. The claimed diffraction positions are the physical consequences of the crystal lattice of the material being measured, rather than an independently added compositional ingredient.
The rejection is therefore not premised on an assertion that it would have been “routine to search for and discover any polymorph.” Rather, it is based on Jackson's disclosure of the pre-existing crystalline calcium D-glycerate dihydrate and the determination that recitation of previously unreported physical characteristics of that old material does not distinguish the product where those characteristics are necessarily possessed by the old material.
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.
Claims 22-27 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 specific preparation of amorphous calcium D-glycerate exemplified in Example 4 and closely related embodiments, does not reasonably provide enablement for the full scope of the methods presently claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 22 recites preparing an amorphous form of calcium glycerate by stirring a crystalline form of calcium glycerate with “a solvent” at a first temperature for a first time period to form a suspension, filtering to form a supersaturated solution, stirring and cooling the supersaturated solution, aging and filtering the solution, and drying the product to obtain the amorphous form. The claim does not limit the identity or physicochemical properties of the solvent and does not limit the first temperature, first time period, stirring rate, cooling rate, second temperature, second aging period, drying pressure, drying temperature, or drying time.
The specification provides considerably narrower guidance. Paragraphs [0061]–[0066] describe preparation of Form III and identify methanol, ethanol, acetonitrile, acetone, dimethyl sulfoxide, and N,N-dimethylformamide as exemplary solvents; a first temperature of 20–60°C, preferably 40–50°C; a first time period of 20–120 minutes, preferably 60–90 minutes; stirring at 40–120 r/min; cooling at 40–90°C/h; a second temperature of −10 to 10°C; aging for 1–10 hours; and specified drying pressure, temperature, and time ranges. Paragraph [0066] states that Cu-Kα XRPD of Form III indicates that the resulting material is amorphous.
Only one actual preparation of the amorphous material is provided. Example 4, paragraph [0076], employs calcium D-glycerate Form I or II specifically in anhydrous methanol, at 45°C for 60 minutes, followed by stirring at 90 r/min, cooling at 70°C/h to 5±0.2°C, aging for 5 hours, and drying at 35°C and −0.085 MPa for 4 hours. No working example demonstrates production of the claimed amorphous calcium glycerate using ethanol, acetonitrile, acetone, DMSO, DMF, or any other solvent, and no working example demonstrates that substantially different combinations of temperature, supersaturation, cooling, aging, and drying conditions produce the same amorphous material. Spec. ¶ [0076].
The enablement determination is made by considering the factors identified in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988), including the breadth of the claims, nature of the invention, state of the prior art, level of ordinary skill, predictability of the art, amount of guidance provided, existence of working examples, and quantity of experimentation necessary. MPEP § 2164.01(a). A single working example does not by itself establish nonenablement; however, where the claim extends materially beyond that example, the Office must determine whether the disclosure provides sufficient guidance to permit extrapolation across the claimed scope without undue experimentation. (USPTO)
With respect to the breadth of the claims, claim 22 is substantially broader than the disclosed working example. The term “a solvent” is not limited to the six solvent species discussed in paragraph [0063], nor is it limited by polarity, water content, calcium-glycerate solubility, dielectric constant, proticity, or another property bearing on whether the required supersaturated solution and amorphous solid will be obtained. Claim 22 also leaves the principal crystallization/amorphization process variables unrestricted.
With respect to the nature and predictability of the invention, the claimed subject matter concerns solid-state conversion of crystalline calcium glycerate into an amorphous material through solvent treatment, supersaturation, rapid cooling, aging, filtration, and drying. The specification itself demonstrates that calcium D-glycerate can exist as materially different solid forms and employs different solvent and processing conditions to obtain Forms I, II, and III. For example, Form II is prepared using acidification, methanol, reflux and controlled cooling, whereas Form III is obtained by a different solvent/supersaturation and rapid-cooling procedure. Spec. ¶¶ [0054]–[0066], [0073]–[0076]. This indicates that solid-form outcome depends upon the solvent and processing conditions rather than flowing predictably from the chemical identity of calcium glycerate alone.
With respect to the amount of direction and guidance, paragraphs [0062]–[0065] provide possible solvents and broad ranges but do not disclose criteria by which a skilled artisan could determine, without experimentation, which solvents and combinations of temperature, concentration, supersaturation, cooling rate, aging conditions, and drying conditions will produce the amorphous material rather than Form I, Form II, another crystalline form, a mixture of forms, or no isolated solid. The specification does not identify a required solubility relationship, degree of supersaturation, water activity, critical cooling rate, nucleation criterion, or other general principle that would permit the skilled artisan to extrapolate the methanol Example 4 procedure throughout the scope of claim 22. Spec. ¶¶ [0062]–[0066].
With respect to the working examples, only the anhydrous-methanol procedure of paragraph [0076] is demonstrated. The rejection is therefore not based merely on the presence of a single working example, but on the combination of the broad unrestricted claim scope, the solid-form sensitivity demonstrated by the specification, the absence of a disclosed relationship permitting prediction of successful solvent/process combinations, and the resulting amount of screening necessary to determine which embodiments actually yield the claimed amorphous product. MPEP § 2164.01(a) expressly provides that a single example may support a scope narrower than the claim where the facts do not reasonably permit extrapolation over the full claimed scope.
With respect to the quantity of experimentation, practicing claim 22 throughout its scope would require selecting and testing solvents across potentially diverse chemical classes, determining appropriate solubility and supersaturation conditions for each solvent, varying temperature and residence time, determining suitable cooling and aging conditions, varying the drying conditions, and then analytically determining whether the recovered material is amorphous. Such experimentation is not merely verification of an otherwise taught embodiment; it amounts to identifying operable combinations within a broad multidimensional process space for which the specification supplies only one demonstrated combination.
The level of ordinary skill in the crystallization and pharmaceutical solid-state arts is recognized as relatively high. This factor weighs in favor of enablement. Nevertheless, even a skilled artisan must be provided sufficient disclosure to practice the full claimed scope without undue experimentation. The specification does not establish that an ordinarily skilled artisan could predict, from the single methanol example or from the generic solvent list, which of the numerous combinations encompassed by claim 22 will reproducibly provide the claimed amorphous calcium glycerate. MPEP § 2164.08 requires reasonable enablement commensurate with the scope sought, and the Supreme Court has reiterated that the broader the claimed scope, the more the specification must enable.
Claim 23 does not overcome this deficiency. Although claim 23 recites the six specifically identified solvents, the limitations are stated disjunctively: the first temperature is within a specified range, or the solvent is one of the listed solvents, or the first time period is within a specified range. Thus, claim 23 continues to encompass embodiments employing an otherwise unrestricted solvent whenever one of the other alternative limitations is met.
Claims 24–27 likewise depend from claim 22 and add particular process parameters or starting crystalline forms but do not require the solvent to be anhydrous methanol or otherwise restrict the solvent sufficiently to the demonstrated enabled embodiment. Claims 24–27 therefore continue to encompass the nonenabled scope discussed above.
Accordingly, although the disclosure is considered enabling for the specific anhydrous-methanol process demonstrated in Example 4 and reasonably similar embodiments, the disclosure does not reasonably enable the full scope of claims 22–27 without undue experimentation. Claims 22–27 are therefore rejected under 35 U.S.C. 112(a).
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 1-7, 10, 13-18, 25 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 defines crystalline Form I by XRPD diffraction peaks stated as numerical 2θ values of 12.9°±0.2°, 20.9°±0.2°, and 31.7°±0.2°. Claims 2 and 3 recite additional numerical 2θ peak positions, and claims 4–7, 10, and 13 ultimately depend from claim 1 and therefore incorporate the same XRPD limitation.
Claim 14 similarly defines crystalline Form II by numerical XRPD peak positions of 15.4°±0.2°, 17.0°±0.2°, and 27.1°±0.2°. Claims 15 and 16 recite additional numerical 2θ peak positions, and claims 17 and 18 depend from claim 14 and therefore incorporate the XRPD limitation of claim 14.
The claims do not identify the X-ray radiation source or wavelength used to obtain the stated numerical 2θ values.
This omission is material because 2θ is not a wavelength-independent property. Under Bragg's law, nλ = 2d sinθ, such that the diffraction angle θ for a given lattice spacing d depends upon the wavelength λ of the incident radiation. Thus, changing the radiation wavelength changes the numerical 2θ value associated with a particular crystallographic plane. (NIST)
The specification confirms the materiality of this measurement condition. Paragraph [0037] states expressly that “by using Cu-Kα radiation” crystalline Form I has the recited 12.9°, 20.9°, and 31.7° XRPD peaks. Paragraphs [0038] and [0039] provide the additional Form-I peaks. Likewise, paragraph [0050] expressly states that “by using Cu-Kα radiation” crystalline Form II has the 15.4°, 17.0°, and 27.1° peaks, with paragraphs [0051] and [0052] supplying the additional Form-II peaks.
Accordingly, the specification expressly ties the numerical peak positions used to identify Forms I and II to Cu-Kα radiation, while the claims merely recite the numerical 2θ values without stating the radiation source. The claim language therefore leaves uncertain whether the recited ranges are to be determined using the Cu-Kα radiation expressly employed by the specification, or whether a material measured using another X-ray wavelength would nevertheless be required to exhibit the same numerical 2θ positions.
Because the numerical 2θ values change as a function of wavelength, the omitted measurement condition affects whether a particular crystalline material falls within or outside the claims. The boundaries of the claims therefore cannot be determined with the requisite clarity from the claim language itself.
Claim 25 recites:
“the second temperature ranges from −10°C to 10°C/h or from 0°C to 8°C.”
The recitation “−10°C to 10°C/h” is indefinite because the lower endpoint, −10°C, is a temperature, whereas the upper endpoint, 10°C/h, is a rate of temperature change. These quantities have different dimensions and therefore cannot define the endpoints of a single temperature range. It is consequently unclear whether the claim is intended to require a second temperature of −10°C to 10°C or is intended to impose some limitation on cooling rate.
The specification establishes that these are separate parameters. Paragraph [0065] states that the cooling rate may range from 40°C/h to 90°C/h, or from 60°C/h to 80°C/h, whereas the second temperature may range from −10°C to 10°C, or from 0°C to 8°C. Spec. ¶ [0065].
Thus, the specification supports “10°C” as the upper endpoint of the second-temperature range, while the presently claimed “10°C/h” introduces a dimensionally different parameter. Because it cannot be determined from the claim whether the limitation is directed to temperature or rate of temperature change, the metes and bounds of claim 25 are unclear.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEBORAH D CARR whose telephone number is (571)272-0637. The examiner can normally be reached Monday-Friday (10:30 am -6:30 pm).
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/DEBORAH D CARR/Primary Examiner, Art Unit 1691
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