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 .
Priority
The present application, filed October 26, 2023, is a national stage application of PCT/IB2022/053336, filed April 9, 2022, and claims priority to foreign priority application IN 202141019490, filed April 28, 2021.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in the Republic of India on April 28, 2021. It is noted, however, that applicant has not filed a certified copy of application IN 202141019490 as required by 37 CFR 1.55.
Status of the Application
Applicant’s preliminary amendment, received October 26, 2023, wherein claims 1-6 are amended, is acknowledged.
Claims 1-9 are pending and examined on the merits herein.
Specification
The disclosure is objected to because of the following informalities: The structure of Cladribine shown on p. 1, line 24 is a low resolution structure. Please replace this structure with a higher resolution structure.
Appropriate correction is required.
Drawings
The drawings are objected to because Figures 2, 4, and 5 include axes labels and/or labels on the figures wherein the text is difficult to interpret. Please replace Figures 2, 4, and 5 with figures that include high resolution text.
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 Interpretation
The present claims 1-6 require an amorphous cladribine complex. In the absence of an express definition provided in the specification, the term complex is interpreted consistent with its customary meaning in the art. Britannica (Brittanica entry for “complex” cited in PTO-892) teaches that a complex, in chemistry, is a substance, formed by the union of simpler substances (as compounds or ions) and held together by forces that are chemical.
Therefore, any chemical interaction of two compounds in a composition, such as cladribine in composition with a pharmaceutically acceptable excipient, is interpreted herein as a complex.
Claim Objections
Claims 1-4 and 8-9 are objected to because of the following informalities:
Claim 1 recites: “wherein the amorphous cladribine complex having percentage of crystallinity less than 2% (w/w).” Please amend this limitation to recite: “wherein the amorphous cladribine complex has a percentage of crystallinity less than 2% (w/w).”
In addition, the chemical structure shown in claim 1 is of low resolution. Please replace this structure with a higher resolution structure.
Furthermore, claim 1 appears to include a period in line 2 following “excipient.” MPEP 608.01(m) states: “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).” Please amend claim 1 to comply with this requirement.
Claims 2 and 3 recite: “A process for the preparation of stable pharmaceutical composition of amorphous Cladribine complex of Formula (1) comprises:”. Please amend claim 2 to recite: “A process for the preparation of a stable pharmaceutical composition of amorphous Cladribine complex of Formula (1) comprising:”.
Claim 3 recites: “wherein the amorphous cladribine complex is having% of crystallinity less than 2%(w/w).” Please amend this limitation to recite “wherein the amorphous cladribine complex has a % of crystallinity less than 2% (w/w).”
Claim 4 recites: “wherein suitable solvent in step a) is selected from alcohols, esters, ketones, hydrocarbons, water, or mixtures thereof.” Please amend to recite “wherein the suitable solvent in step a) is selected from alcohols, esters, ketones, hydrocarbons, water, or mixtures thereof.”
Claim 8 recites “The solid dispersion of claim 7, wherein the dispersing agent comprises HPBCD, hydroxypropyl methyl cellulose (HPMC), Polyvinyl pyrrolidone (PVP), Colloidal silicon dioxide and the like.” The examiner believes HPBCD refers to hydroxypropyl-β-cyclodextrin, as stated in the specification (p. 3, line 8). Please amend HPBCD to recite HPβCD.
Claim 9 recites: “A pharmaceutical composition comprising solid dispersion of claim 7.” Please amend claim 9 to recite: “A pharmaceutical composition comprising the solid dispersion of claim 7.”
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 1-6, and 8 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 recites an amorphous cladribine complex of Formula (1) with at least one
pharmaceutically acceptable excipient.” This is indefinite because it is unclear if the cladribine complex of formula (I) is required to include an additional component in order to form a complex with cladribine, which then must be combined with the at least one pharmaceutically acceptable excipient, or if the amorphous cladribine complex of Formula (1) is formed from Cladribine and the at least one pharmaceutically acceptable excipient.
Claim 2 recites in step b): “removing the solvent from the solution obtained in step a).” There is insufficient antecedent basis for this limitation in the claim because step a) does not recite a solvent, only a pharmaceutically acceptable excipient as a dispersing agent.
Because claims 4-6 depend from claim 2 and fail to cure the above deficiency, claims 4-6 are also indefinite.
Moreover, claims 2 and 3 are each independent claims and recite amorphous cladribine complex of Formula (I). There is insufficient antecedent basis for this limitation in the claim because neither of claims 2 or 3 define what is required by the amorphous cladribine complex of Formula (I). Claim 1 claims an amorphous cladribine complex of Formula (1), but claims 2 and 3 do not depend from claim 1. The examiner believes that this complex only requires amorphous cladribine with a pharmaceutically acceptable excipient or dispersing agent, as recited in claims 2 and 3.
Claims 2 and 3 recite: “A process for the preparation of stable pharmaceutical composition of amorphous Cladribine complex of Formula (I) comprising:…”. The term “stable” in claims 2 and 3 is a relative term which renders these claims indefinite. The term “stable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For example, one of ordinary skill in the art would not recognize the specific conditions or the minimum amount of time under which the pharmaceutical composition must retain specific properties in order to be considered as “stable.”
Claim 3 recites: A process for the preparation of stable pharmaceutical composition of
amorphous Cladribine complex of Formula (1) comprises: a) mixing Cladribine with a suitable dispersing agent or pharmaceutically acceptable salt; b) blending or grinding the mixture to obtain amorphous Cladribine complex with pharmaceutically suitable agent; wherein the amorphous cladribine complex is having% of crystallinity less than 2% (w/w). There is insufficient basis for “pharmaceutically suitable agent” recited in step b) of claim 3. “Pharmaceutically suitable agent” is not recited in the preamble or step a) of the claim. The examiner believes “pharmaceutically suitable agent” is intended to refer to “suitable dispersing agent” as recited in step a) of claim 3.
Claim 4 depends from claim 2 and recites the limitation "suitable solvent in step a)" in line 1 of the claim. There is insufficient antecedent basis for this limitation in the claim because step a) of claim 2 does not require a solvent, only a pharmaceutically acceptable excipient as a dispersing agent.
Claim 6 recites: “wherein step c) involves an additional step of drying the isolated Cladribine with suitable dispersing agent.” There is insufficient antecedent basis for this limitation in the claim because step c) of claim 2 does not recite the isolated Cladribine with suitable dispersing agent, but instead recites “amorphous form of Cladribine complex of formula (1).”
Claims 2, 3, 4, 5, and 6 recite the terms “suitable pharmaceutically acceptable excipient,” “suitable dispersing agent,” “pharmaceutically suitable agent,” “suitable solvent,” and “suitable anti-solvent.” The term “suitable” in these claims is a relative term which renders these claims indefinite. The term “suitable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For example, one of ordinary skill in the art would not recognize the specific properties a pharmaceutically acceptable excipient, dispersing agent, pharmaceutical agent, solvent, or anti-solvent must possess in order to be considered as “suitable.”
Regarding claim 8, the phrase "and the like" renders the claim(s) indefinite because the claim(s) include(s) elements not actually disclosed (those encompassed by "and the like"), thereby rendering the scope of the claim(s) unascertainable. See MPEP § 2173.05(d).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-9 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Bodor (U.S. pre-grant publication no. US 20070197468 A1; cited in PTO-892).
Claim 1 claims an amorphous Cladribine complex of Formula (1) with at least one
pharmaceutically acceptable excipient, wherein the amorphous cladribine complex has a percentage of crystallinity less than 2% (w/w).
Claim 3 claims a process for the preparation of stable pharmaceutical composition of
amorphous Cladribine complex of Formula (1) comprising: a) mixing Cladribine with a suitable dispersing agent or pharmaceutically acceptable salt; b) blending or grinding the mixture to obtain amorphous Cladribine complex with pharmaceutically suitable agent; wherein the amorphous cladribine complex has a % of crystallinity less than 2% (w/w).
Bodor teaches and claims a pharmaceutical composition obtainable by a process
comprising the steps of: (i) combining cladribine and an amorphous cyclodextrin in water at a temperature of from about 40 to about 80° C and maintaining said temperature for a period of
from about 6 to about 24 hours; (ii) cooling the resultant aqueous solution to room temperature;
(iii) lyophilizing the cooled solution to afford an amorphous product; and (iv) formulating the amorphous product into a solid oral dosage form (p. 14, claim 82). Bodor further teaches and claims this pharmaceutical composition, wherein formulation step (iv) of the process comprises blending the complex with magnesium stearate and compressing into tablets (p. 14, claim 97).
Step i) of the method of Bodor satisfies step a) of claim 3, and step iv) of the method of Bodor satisfies step b of claim 3).
Regarding the requirement of claims 1 and 3 that the amorphous cladribine complex has a percentage of crystallinity less than 2% (w/w), Bodor teaches products FD04 and FD05, which were prepared by heating water, adding 2-hydroxypropyl-β-cyclodextrin and stirring until dissolution, adding cladribine, and stirring for approximately 9 hours with heating and 7 hours while the solution cooled (p. 9, [0082]). Bodor teaches that after cooling to room temperature and, for composition FD05, filtering, the solutions were filled into lyophilization vials and lyophilized (p. 9, [0084]). This method of preparing FD04 and FD05 includes steps (i)-(iii) recited in claim 82 above.
Bodor teaches that their products FD04 and FD05 were analyzed by DSC thermograms and X-ray diffraction methods to determine any free crystalline cladribine in the lyophilized material. Bodor teaches that, importantly, the samples exhibited no transitions in the region of 210° C to 230° C, which is associated with the melting of crystalline cladribine and that in both cases, no significant thermal activity was recorded in the range of 210° C to 230° C. Bodor teaches this suggests that the complexes obtained at the end of the lyophilization do not have any significant amount of free crystalline cladribine, considering the sensitivity of the analytical method (up to 3% w/w). Bodor teaches that this conclusion was supported by the absence of peaks for crystalline cladribine from X-ray diffraction traces for both complexes FD04 and FD05 (p. 9, [0086], lines 1-13).
MPEP 2112.01 (especially at I) citing In re Best, 562 F.2d 1252, 195 USPQ 430
(C.C.P.A. 1977) and In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)
discusses the support of rejections wherein the prior art discloses subject matter which there is
reason to believe inherently includes functions or characteristics that are newly recited or
identical to an invention instantly claimed. In such a situation the burden is shifted to the
applicants to show the invention of the applicant and the prior art are not the same or that the
prior art products do not necessarily possess the characteristics of the claimed invention.
In this instance, although Bodor does not specifically teach having a crystallinity less than 2% (w/w), because Bodor teaches their isolated solid dispersion product exhibited no transitions in the region of 210° C to 230° C, and that the sensitivity of their method allows them to conclude their composition does not include crystalline cladribine at more than 3% (w/w), it is believed that the product of Bodor inherently has a crystallinity less than 2% (w/w), absent evidence to the contrary.
Moreover, because FD04 and FD05 were prepared using steps (i)-(iii) recited in claim 82, the amorphous product formulated in step (iv) by blending with magnesium stearate (as recited on 14, claim 97) would also have provided a pharmaceutical composition with a crystallinity less than 2% (w/w), because blending an amorphous composition with an additional excipient would not have been expected to increase the crystallinity present in the composition, absent evidence to the contrary.
Thus Bodor anticipates claims 1 and 3.
Present claim 2 claims a process for the preparation of stable pharmaceutical composition of amorphous Cladribine complex of Formula (1) comprises: a) providing a solution of Cladribine in a suitable pharmaceutically acceptable excipient as dispersing agent; b) removing the solvent from the solution obtained in step a); and c) recovering amorphous form of Cladribine complex of formula (I). Claim 4 requires the suitable solvent in step a) is selected from alcohols, esters, ketones, hydrocarbons, water, or mixtures thereof. Claim 5 requires wherein removal of solvent in step b) is affected by evaporation, freeze drying, spray drying, lyophilization, by addition of suitable anti-solvent or any combination thereof. Claim 6 requires step c) involves an additional step of drying the isolated Cladribine with suitable dispersing agent.
Bodor teaches and claims a process for the preparation of a complex cladribine-cyclodextrin complex which comprises the steps of: (i) combining cladribine and an amorphous cyclodextrin in water at a temperature of from about 40 to about 80° C and maintaining said temperature for a period of from about 6 to about 24 hours; (ii) cooling the resultant aqueous solution to room temperature; and (iii) lyophilizing the cooled solution to afford an amorphous product (pp. 12-13, claim 67).
This process satisfies all limitations of the method of claim 2, includes water as a solvent as required by claim 4, and includes the step of lyophilization as required by claim 5.
Regarding claim 6, which requires the additional step of drying the isolated Cladribine with dispersing agent, Bodor teaches that their lyophilization method involves a secondary drying phase at 30 °C (p. 9, [0084], see lines 4-9 and Table 1). Because Bodor teaches lyophilizing their solution to afford an amorphous product in claim 67 as described above, and because Bodor teaches their method of lyophilization involves a secondary drying step, the method of claim 67, together with the lyophilization process disclosed by Bodor, would also satisfy the limitations of claim 6.
Moreover, as described above, Bodor teaches FD04 was prepared by heating water, adding 2-hydroxypropyl-β-cyclodextrin and stirring until dissolution, adding cladribine, and stirring for approximately 9 hours with heating and 7 hours while the solution cooled (p. 9, [0082]). Bodor teaches that after cooling to room temperature, the solutions were filled into lyophilization vials and lyophilized (p. 9, [0084]) using the lyophilization program outlined in Table 1 which includes the step of secondary drying (p. 9, [0084], Table 1). This method satisfies all limitations of claims 2 and 4-6, wherein the 2-hydroxypropyl-β-cyclodextrin is the dispersing agent, water is the solvent, and the secondary drying step following lyophilization is the additional step of drying as recited in claim 6.
Thus Bodor anticipates claims 2 and 4-6.
Claim 7 claims a solid dispersion comprising amorphous Cladribine in a dispersing agent. Claim 8 requires the dispersing agent comprises HPβCD, hydroxypropyl methyl cellulose (HPMC), Polyvinyl pyrrolidone (PVP), Colloidal silicon dioxide and the like, and claim 9 requires a pharmaceutical composition comprising solid dispersion of claim 7.
Bodor teaches and claims a pharmaceutical composition comprising a complex cladribine-cyclodextrin complex which is an amorphous admixture of (a) an amorphous inclusion complex of cladribine with an amorphous cyclodextrin and (b) amorphous free cladribine associated with amorphous cyclodextrin as a non-inclusion complex, formulated into a solid oral dosage form (p. 12, claim 1). Bodor further claims the amorphous cyclodextrin is selected from a group that includes hydroxypropyl-β-cyclodextrin (p. 12, claim 3). This product satisfies all structural limitations of a solid dispersion as recited in claims 7-9.
Thus Bodor anticipates claims 7-9.
Claims 1-2, 4-5, 7, and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rost (Publication no. EP 3628310 A1; cited in IDS received October 26, 2020).
Rost teaches an embodiment in which 5.0 g of Linecaps was dissolved in 25 ml of distilled water under stirring conditions at room temperature, followed by addition of 10 ml of ethanol. Rost teaches 0.5 g cladribine was suspended in the Linecaps:water:ethanol solution and heated to 50° C. Rost teaches that once the solution was clear, the solution was pumped into the spray-drier, where the solvent was instantaneously evaporated and a solid product was collected (p. 6, [0071], lines 1-4). Rost teaches that an analogous process was performed using isopropanol instead of ethanol (p. 6, [0072], line 1).
Rost teaches that Kleptose® Linecaps is maltodextrin from pea starch and is rich in linear and soluble amylose (p. 5, [0047], line 1).
Rost teaches and claims a pharmaceutical composition comprising a solid dispersion of amorphous cladribine and a water-soluble pharmaceutically acceptable carrier (p. 7, claim 1), and further teaches and claims the water-soluble pharmaceutically acceptable carrier is spray-dried high amylose pea maltodextrin (p. 7, claim 2). Linecaps is thus reasonably interpreted as a pharmaceutically acceptable excipient, as required by independent claims 1-2.
Therefore, this method taught by Rost of preparing the pharmaceutical composition comprising a solid dispersion satisfies the limitations of claims 2 and 4-5.
Moreover, Rost teaches that XRD data of sample b) and sample d) prepared from the method above (which correspond to the product of the above method prepared from water/ethanol and water/isopropanol, respectively; see p. 6, [0073]) show the isolated solid dispersion product was fully amorphous, and that same results were achieved when vacuum evaporation or spray drying were applied for drying/solvent removal (p. 6, [0074], lines 1-3) (emphasis added). This is taken as teaching that samples b) and d) taught by Rost, as fully amorphous, had a percentage of crystallinity less than 2% (w/w).
MPEP 2112.01 (especially at I) citing In re Best, 562 F.2d 1252, 195 USPQ 430
(C.C.P.A. 1977) and In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)
discusses the support of rejections wherein the prior art discloses subject matter which there is
reason to believe inherently includes functions or characteristics that are newly recited or
identical to an invention instantly claimed. In such a situation the burden is shifted to the
applicants to show the invention of the applicant and the prior art are not the same or that the
prior art products do not necessarily possess the characteristics of the claimed invention.
In this instance, although Rost does not specifically teach having a crystallinity less than 2% (w/w), because Rost teaches their isolated solid dispersion product was fully amorphous, it is believed that the composition of Rost produces a product that has a crystallinity less than 2% (w/w), absent evidence to the contrary. Thus the composition of Rost satisfies the limitations of claim 1.
Regarding the solid dispersion of claims 7 and 9, Rost discloses their pharmaceutical composition as a solid dispersion of amorphous cladribine and a water-soluble carrier, wherein the water-soluble carrier may be in particular spray-dried high amylose pea maltodextrin (p. 2, [0001], lines 1-3). High amylose pea maltodextrin is reasonably considered as a dispersing agent, because it is present in the solid dispersion with cladribine disclosed by Rost.
Thus Rost anticipates claims 1-2, 4-5, 7, and 9.
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 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Bodor (U.S. pre-grant publication no. US 20070197468 A1; cited in PTO-892) in view of Rost (Publication no. EP 3628310 A1; cited in IDS received October 26, 2020).
The examiner believes that Bodor anticipates claims 1 and 3, as described in the above rejection under 35 U.S.C. 102. However, for the sake of argument, if, for example, Bodor does not anticipate claims 1 and 3 because Bodor’s teaching their product exhibited no transitions in the region of 210° C to 230° C does not conclude their composition had crystallinity less than 2% (w/w), then claims 1 and 3 would have been obvious over Bodor in view of Rost.
Bodor teaches as described in the above rejection under 35 U.S.C. 102.
Bodor does not expressly teach their compositions as having crystallinity of less than 2% (w/w), as required by claims 1 and 3.
Rost teaches as described in the above rejection under 35 U.S.C. 102. In addition, Rost teaches the benefits of solid dispersions and amorphous pharmaceutical formulations. Rost teaches that one of the underlying principles of formulations of solid dispersions is the generation of the amorphous state, which is considered to be more soluble than the crystalline state because in the amorphous state, no energy is required to break the crystal lattice found in the crystalline phase (p. 3, [0015], lines 1-3) (emphasis added).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to prepare the pharmaceutical composition of Bodor comprising amorphous cladribine and amorphous hydroxypropyl-β-cyclodextrin with as little crystalline material as possible. One of ordinary skill in the art would have been motivated to prepare the pharmaceutical composition of Bodor comprising amorphous cladribine and amorphous hydroxypropyl-β-cyclodextrin with as little crystalline material as possible because Bodor teaches their compositions do not have any significant amount of free crystalline cladribine, and because Rost teaches that solid dispersions in an amorphous state are considered to be more soluble than the crystalline state. Accordingly, because Rost teaches that amorphous solid dispersions as more soluble than crystalline solid dispersions, one of ordinary skill in the art would have recognized that crystalline material present in a composition may reduce the solubility of cladribine in the composition of claim 1 or the product of the method of claim 3, and thus would have optimized the method of Bodor to minimize the crystallinity present in said composition or product.
Therefore the invention taken as a whole is prima facie obvious.
Claims 1-2 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Rost (Publication no. EP 3628310 A1; cited in IDS received October 26, 2020).
The examiner believes that Rost anticipates claims 1, as described in the above rejection under 35 U.S.C. 102. However, for the sake of argument, if, for example, Rost does not anticipate claim 1 because the limitation of Rost’s disclosure that their solid dispersions were fully amorphous is insufficient for concluding their composition had crystallinity less than 2% (w/w), then claim 1 would have been obvious over Rost.
Moreover, claim 2 is included in this rejection because claim 6 depends from claim 2. However, claim 2 is also anticipated by Rost, as described in the above rejection under 35 U.S.C. 103.
Rost teaches as described in the above rejections under 35 U.S.C. 102 and 35 U.S.C. 103. In addition, Rost teaches their general method, which includes the steps of a) providing a solution containing cladribine and a pharmaceutically acceptable carrier in a solvent or a mixture of solvents; b) removing the solvent from the solution of a); and c) optionally drying a solid formed in b) to afford the desired amorphous solid dispersion of cladribine (p. 4, lines 51-56) (emphasis added).
Rost does not teach a specific embodiment in which the pharmaceutical composition disclosed by Rost is prepared using the optional step c) above, as required by claim 6.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to add the additional step of drying the obtained amorphous solid dispersion of cladribine when preparing the pharmaceutical composition disclosed by Rost. One of ordinary skill in the art would have been motivated to add the additional step of drying the obtained amorphous solid dispersion of cladribine when preparing the pharmaceutical composition disclosed by Rost because Rost suggests an optional step c) of drying the solid performed by their method, and accordingly, one of ordinary skill in the art would have reasonably considered adding this additional step to the method taught by Rost in order to obtain a fully dry amorphous solid dispersion of cladribine.
Regarding the requirement of claim 1 that the composition has crystallinity less than 2% (w/w), it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to prepare the pharmaceutical composition of Rost comprising amorphous cladribine and high amylose pea maltodextrin with as little crystalline material as possible. One of ordinary skill in the art would have been motivated to prepare the pharmaceutical composition of Rost comprising amorphous cladribine and high amylose pea maltodextrin with as little crystalline material as possible because Rost teaches their compositions as fully amorphous, and because Rost teaches that solid dispersions in an amorphous state are considered to be more soluble than the crystalline state. Accordingly, because Rost teaches the increased solubility of amorphous solid dispersions compared with crystalline solid dispersions, one of ordinary skill in the art would have recognized crystalline material present in their composition may reduce the solubility of cladribine, and thus would have optimized the method of Rost to minimize the crystallinity present in said composition or product.
Therefore the invention taken as a whole is prima facie obvious.
Conclusion
No claims are allowed.
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/B.M.B./ Examiner, Art Unit 1693
/ANDREA OLSON/ Primary Examiner, Art Unit 1693