DETAILED ACTION
Claims 1, 5-6, and 8-20 are pending. Of these, claims 12-20 are withdrawn as directed to a nonelected invention. Therefore, claims 1, 5-6, and 8-11 are under consideration on the merits.
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 Rejections
The claim objection is withdrawn in view of the amendment.
The 35 USC 112(b) rejection is withdrawn in view of the amendment.
The 103 rejections are revised in view of the amendments.
Claim Objections
Claim 1 is objected to because of the following informalities:
In the last line of the claim, “in” should be deleted. 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 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as 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.
Claims 1-120 each recite “ultra-low dose” of the active. This limitation is unclear because it is unknown how low the dose of the active must be in order to qualify as “ultra-low dose.” The specification fails to provide any formal definition of this term, nor is “ultra-low dose” a term with an art-established definition which could inform the skilled artisan as to the metes and bounds of the claims. While the specification teaches at paragraph 8 as published that the dosage can be “about 175 fold to about 250 fold lower than a chemotherapeutic dosage of the TKI,” this is disclosed as merely “one illustrative embodiment,” leaving it unclear what other embodiments would be within the scope of the claims. The specification also discloses exemplary daily doses of the claimed invention from 0.001 to 3000 mg/kg of body weight (paragraphs 28-29 as published), but nowhere indicates which dosages within this extremely broad range would qualify as an “ultra-low dose” as required by the claims. Paragraph 29 discloses a dose of between 0.24-2.4 mg/day, but nowhere is it indicated whether an “ultra-low dose” is restricted to a dose that is within this range. Additionally, given that claims 1 and 12 recite that the composition is a “pediatric,” it is unclear whether the term “ultra-low doses” refers to an ultra-low dose relative to a standard adult dosage or rather refers to an ultra-low dose compared to a conventional pediatric dosage. Clarification is required. For the purpose of examination in view of the prior art, this limitation has been interpreted as meaning a dose that is significantly lower than the conventional dosage for tyrosine kinases when used for chemotherapeutic purposes for a pediatric patient, for example, a dosage of 0.24-2.4 mg.
Claim 6 recites that the nonpareil seeds are coated with “more than an equal amount by weight of said tyrosine kinase inhibitor,” the meaning of which is unclear because it is unknown what the limitation is with respect to, e.g., is it with respect to the weight of the uncoated nonpareil seeds? Clarification is required.
Claim 7 recites that “approximately 1% of said tyrosine kinase inhibitor is coated onto the nonpareils.” The meaning of this limitation is unclear, firstly, because no units are given for the percent value, e.g., is it a weight percent, and if so, what is it with respect to, e.g., is it by total weight of the dosage form? By total weight of the nonpareils? Alternatively, does the claim language mean that 1% of the tyrosine kinase is coated onto the nonpareils while the remaining 99% is located elsewhere in the composition? Clarification is required.
Claim 8 recites “coated spheres.” There is no antecedent basis for this limitation, as base claim 1 recites that it is the “nonpareil seed” that is coated. Clarification is required.
Claim 12 recites “the Wurster coater insert.” There is no antecedent basis for this limitation. Clarification is required.
Claim 18 recites approximately “1% dasatinib,” which is indefinite because no units are specified, e.g., is it 1 wt% by total weight of the suspension? Clarification is required.
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 and 6-9 are rejected under 35 U.S.C. 103 as unpatentable over Goldstein et al. (US Pat. Pub. 2017/0129890; of record in IDS) in view of Yi et al. (JCI Insight (2016); of record in IDS).
As to claims 1-4 and 6-9, Goldstein discloses a pharmaceutical composition comprising a tyrosine kinase inhibitor active agent (paragraph 2) such as imatinib (claims 2-3)(paragraph 265), the composition comprising pellets comprising nonpareil seeds coated with the active agent (paragraph 232). The pellets further may be coated with hydroxypropylmethyl cellulose as recited by claim 1 to provide for delayed release of the active (paragraph 255). The final composition may be provided as a capsule comprising the pellets (claim 9), which is also a “single dosage unit” of claim 1 (paragraphs 194 and 231). Goldstein teaches that the active may be present in the amount of 0.01-99.9 wt%, such as about 1-80 wt%, based on the total weight of the formulation (paragraph 260).
Regarding the recitation of claim 1 that each pellet “consists essentially of” a coating of the tyrosine kinase inhibitor, while Goldstein discloses that the active agent in the coating over the seeds may comprise further components (paragraph 233), Goldstein does not require the presence of any additional ingredients, thus meeting the “consists essentially of” language.
Regarding the recitation of claim 1 that the HPMC coating “consists essentially of” hydroxypropyl methylcellulose, Goldstein does not require the presence of any additional ingredients in the coating containing the HPMC, thus meeting the “consists essentially of” language.
Additionally, the Office notes that for the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." MPEP 2111.03. See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 ("PPG could have defined the scope of the phrase 'consisting essentially of' for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention."). See also AK Steel Corp. v. Sollac, 344 F.3d 1234, 1240-41, 68 USPQ2d 1280, 1283-84 (Fed. Cir. 2003) (Applicant's statement in the specification that "silicon contents in the coating metal should not exceed about 0.5% by weight" along with a discussion of the deleterious effects of silicon provided basis to conclude that silicon in excess of 0.5% by weight would materially alter the basic and novel properties of the invention. Thus, "consisting essentially of" as recited in the preamble was interpreted to permit no more than 0.5% by weight of silicon in the aluminum coating.); In re Janakirama-Rao, 317 F.2d 951, 954, 137 USPQ 893, 895-96 (CCPA 1963). If an applicant contends that additional steps or materials in the prior art are excluded by the recitation of "consisting essentially of," applicant has the burden of showing that the introduction of additional steps or components would materially change the characteristics of applicant's invention. In re De Lajarte, 337 F.2d 870, 143 USPQ 256 (CCPA 1964). See also Ex parte Hoffman, 12 USPQ2d 1061, 1063-64 (Bd. Pat. App. & Inter. 1989) ("Although 'consisting essentially of' is typically used and defined in the context of compositions of matter, we find nothing intrinsically wrong with the use of such language as a modifier of method steps. . . [rendering] the claim open only for the inclusion of steps which do not materially affect the basic and novel characteristics of the claimed method. To determine the steps included versus excluded the claim must be read in light of the specification. . . . [I]t is an applicant's burden to establish that a step practiced in a prior art method is excluded from his claims by 'consisting essentially of' language.").
Here, the Office has reviewed the specification and could not locate any evidence of a basic and novel characteristics of the invention that would require limiting the scope of “consists essentially of” to be narrower than that of “comprising,” and/or that would exclude the presence of any ingredient that is required by Goldstein to be present in the pellets.
As to claims 1-4 and 6-9, Goldstein does not further expressly disclose that the composition comprises an “ultra-low dose” of the tyrosine kinase inhibitor as recited by claim 1, i.e., a dose that is lower than conventionally used for chemotherapeutic purposes (see 35 USC 112(b) rejection, supra), nor that the tyrosine kinase inhibitor is dasatinib as recited by claim 4.
Yi discloses that administration of the tyrosine kinase inhibitor dasatinib in low doses rescues cardiac function in Noonan syndrome (Title and Abstract), and teaches that daily injection of 0.1 mg/kg for 10 days reduced the levels of PZR tyrosyl phosphorylation compared to vehicle treated control mice, and notes that this result means that dasatinib can target the PXR/SHP2 pathways in the heart at much lower doses than used for chemotherapeutic purposes (page 4, 3rd paragraph).
As to claims 1-4 and 6-9, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the Goldstein composition by selecting an ultra low dose of dasatinib of claim 4 as the tyrosine kinase inhibitor that is below the conventional chemotherapeutic dosage (e.g., 0.1 mg/kg) such as a dosage of 2 mg for a 20 kg child, which would be within the 0.24-2.4 mg exemplary range taught by paragraph 29 of the present specification, with a reasonable expectation of success, because Yi teaches that dasatinib is a tyrosine kinase inhibitor such that the skilled artisan reasonably would have expected that it could serve as the tyrosine kinase inhibitor in the Goldstein composition, and Yi further teaches that a composition comprising such a substantially lower dose of dasatinib relative to a chemotherapeutic composition would have use in rescuing cardiac function in Noonan syndrome. The resulting dosage form is viewed as a pediatric dosage form comprising an “ultra-low dose” of the tyrosine kinase inhibitor as recited by the claims, based upon the evidence of record and in light of the indefiniteness of this term (see 35 USC 112(b) rejection, supra).
Regarding claims 6-8, it further would have been prima facie obvious to select amounts of the tyrosine kinase inhibitor within the recited ranges and amounts, because said amount is a result effective variable that will affect its ability to perform its therapeutic function of rescue cardiac function in Noonan syndrome, such that said amount is subject to an optimization process by the skilled artisan to arrive at the appropriate amount of active per nonpareil that will result in a formulation that will deliver the ultra low dose discussed above. Discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim 5 is rejected under 35 U.S.C. 103 as unpatentable over Goldstein et al. (US Pat. Pub. 2017/0129890; of record in IDS) in view of Yi et al. (JCI Insight (2016); of record in IDS) as applied to claims 1-4 and 6-9 above, and further in view of Hafner et al. (US Pat. Pub. 2016/0168142; of record in IDS).
The teachings of Goldstein are relied upon as discussed above, but Goldstein does not further expressly disclose that the dasatinib is present in an anhydrous form as recited by claim 5.
Hafner discloses salts of dasatinib and teaches that they are useful as tyrosine kinase inhibitors, and teaches that this drug is known to exist in a number of different pharmaceutically useful forms including monohydrate, unsolvated, and anhydrous forms (paragraphs 3-9).
As to claim 5, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the composition of Goldstein and Yi as combined supra by selecting dasatinib that is in its anhydrous form as the tyrosine kinase inhibitor, because Hafner expressly teaches that dasatinib is a tyrosine kinase inhibitor that is known to exist in several different pharmaceutically useful forms including in an anhydrous form, such that the skilled artisan reasonably would have expected that anhydrous dasatinib could serve as the type of tyrosine kinase inhibitor in the pharmaceutical composition of Goldstein. Such a modification is merely the substitution of one known element for another to obtain predictable results, which is prima facie obvious. MPEP 2143.
Claims 10-11 are rejected under 35 U.S.C. 103 as unpatentable over Goldstein et al. (US Pat. Pub. 2017/0129890) in view of Yi et al. (JCI Insight (2016); of record in IDS) as applied to claims 1-4 and 6-9 above, and further in view of Bhargava et al. (EP2127628 (2009)).
The teachings of Goldstein are relied upon as discussed above, but they do not further expressly disclose that the capsules are carded onto a dose pack containing a singular therapeutic dose (claim 10) or multiple therapeutic doses (claim 11).
Bhargava discloses a unit dose pack for holding pharmaceuticals that may be in the form of capsules (Abstract and paragraphs 12 and 18).
As to claims 10-11, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the composition of Goldstein and Yi as combined supra by incorporating the capsules into a dose pack, since Bhargava discloses that dose packs can be used to package pharmaceutical capsule compositions, with a reasonable expectation of success in arriving at a package that will conveniently store the capsules. Selecting the number of doses for incorporation into the dose pack is well within the purview of the skilled artisan depending upon whether the convenience of a single dose per pack or the reduced packaging needs if multiple doses are included per pack is viewed as most desirable. Discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claims 12-21 are rejected under 35 U.S.C. 103 as unpatentable over Goldstein et al. (US Pat. Pub. 2017/0129890; of record in IDS) in view of Yi et al. (JCI Insight (2016); of record in IDS) as applied to claims 1-4 and 6-9 above, and further in view of Ullah et al. (US Pat. Pub. 2001/0024660; of record in IDS).
The teachings of Goldstein and Yi are relied upon as discussed above, and Goldstein further teaches that the non-pareils may be sugar pareils as recited by claim 13 (paragraph 232), that the size of the seeds is not essential and may vary between about 0.1 and 2 mm (paragraph 232), and that the HPMC coating may comprise other ingredients such as fillers (paragraph 233)(“excipients” of claim 19), but Goldstein does not further expressly disclose a method of formulating the dosage form as recited by claim 12, wherein the concentration of the active pharmaceutical ingredient for coating onto the nonpareils is approximately 1% dasatinib, and wherein the nonpareils have a mesh size of 35-45 (claim 13). Additionally, while Goldstein discloses the use of microcrystalline cellulose as diluents in the composition (paragraph 204) and teaches that the nonpareils may be formed from celluloses (paragraph 232), Goldstein does not specify that the cellulose is microcrystalline cellulose as recited by claim 17.
Ullah discloses a pharmaceutical composition comprising enteric coated pellets, wherein the coating is formed by loading the pellets into a fluid bed with a Wurster column, fluidizing the pellets and warming them to a temperature of 64 degrees Celsius, spraying the pellets with a coating solution until a desired weight gain is achieved, and then drying the pellets (paragraphs 46, 54-55). Wurster further teaches screening the pellets through #10 and #20 mesh screens to remove oversized or undersized pellets (paragraph 52). The coating solution comprises water (paragraph 41) and further may comprise excipients such as a plasticizer (paragraph 37) and may be in the form of a dispersion (“suspension” of claims 12 and 18)(paragraph 35).
As to claims 12-15, 17, and 19-21, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the disclosure of Goldstein and Yi as combined supra by formulating the pellet dosage form by loading the pellets into a fluid bed with a Wurster column, fluidizing the pellets and warming followed by spraying the pellets with a coating solution comprising the active as a suspension until a desired weight gain is achieved, drying and screening the coated pellets, and then loading the coated pellets into the fluid bed and applying the seal coating comprising HPMC, excipients, and water to achieve a desired weight gain as recited by claim 12, because Ullah expressly teaches that such a method is suitable for forming coatings on pellets for use in pharmaceutical formulations, such that the skilled artisan reasonably would have expected that the Goldstein seeds could be coated with the active and with the HPMC coat using this method. Such a modification is merely the combining of known prior art elements according to known methods to yield predictable results, which is prima facie obvious. MPEP 2143. Regarding the temperature at which the nonpareils are warmed, Ullah’s disclosure of warming to 64 degrees Celsius is viewed as sufficiently close to the ”approximately 60” degrees Celsius recited by the claims due to the use of the term “approximately,” and because the difference in temperature is small enough that the skilled artisan would have expected that the use of either temperature would result in a composition having substantially the same properties. MPEP 2144.05 I. Differences in concentration or temperature generally will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
The resulting method will allow for human subject dosing on a mg/kg basis as recited by claim 20, since the beads are coated with the tyrosine kinase inhibitor active and therefore an amount of the ultra-low dosage form can be selected that contains the desired amount of the active on a mg/kg basis.
As to claim 13, it further would have been prima facie obvious to select nonpareils having a mesh size of 35-45, because Ullah expressly teaches using mesh screens to remove pellets that are bigger or smaller than the desired size, and Goldstein teaches that sizes between about 0.1 and 2 mm can be used, which encompasses mesh sizes of 35-45. Additionally, discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 17, it further would have been prima facie obvious to use nonpareils made of microcrystalline cellulose, since Goldstein itself teaches that the nonpareils may be formed from celluloses without limiting the nonpareils to any specific type of cellulose, and Goldstein further teaches that microcrystalline cellulose is a type of cellulose that is suitable for use in the composition as a diluent, such that the skilled artisan reasonably would have expected that it could be used as the type of cellulose to form the nonpareils.
As to claim 18, it further would have been prima facie obvious to use a 1% solution of the dasatinib as the coating solution, because the concentration of the dasatinib is a result effective variable that will affect the amount of the dasatinib active that will be deposited onto the nonpareils and therefore the total amount of active in the formulation, which will affect the therapeutic efficacy of the formulation. Differences in concentration or temperature generally will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Conclusion
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/GAREN GOTFREDSON/Examiner, Art Unit 1619
/BENNETT M CELSA/Quality Assurance Specialist , Art Unit 1600