DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
The listing of claims filed 01 March 2023, have been examined. In response to the Requirement for Restriction/Election, dated 21 July 2025, the applicant has elected Group II, claims 15-33, without traverse in the reply filed 20 January 2026, to prosecute the invention drawn to a kit and pharmaceutical formulation/composition containing gamitrinib. The election without traverse is therefore made final and cannot be further petitioned under 37 CFR 1.144.
Claims 1-14 and 34-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention (see also MPEP § 821.03). Claims 15-33 are pending. The preliminary Specification amendment filed 29 December 2023, is also acknowledged.
Information Disclosure Statement
The Information Disclosure Statement (IDS), filed 16 June 2023, is acknowledged and has been considered.
Claim Interpretation
The subject matter of claim 15 is a physical kit comprising gamitrinib and an instruction manual, wherein the manual recites an administration protocol with a dosing phase (standard dosing phase, about 0.1–50 mg/kg/week). The manual’s instructions describe how the kit would be used, but the claim does not require that the administration actually occurs. No active administration step is positively recited.
The phrase “wherein the instruction manual instructs administering” sets a requirement for the content of the manual, not for a step performed on the subject. Under MPEP 2173.05(p), reciting instructions in a kit claim does not convert the claim into a method of treatment. To claim actual administration of gamitrinib, a different claim form is required (e.g., “A method of treating cancer in a subject in need thereof, comprising administering to the subject gamitrinib according to a protocol comprising …”). Therefore, as drafted, claim 15 does not cover actual administration of gamitrinib to a subject (i.e., a method of treatment), rather merely a kit containing it along with an instruction manual.
Claim 15 does not, and cannot without changing statutory category, claim actual administration. For the dependent claims 16-24 to incorporate administration of gamitrinib, the claims would need to depend from a new method claim, separate from claim 15, that incorporates the kit claim 15 by reference would be required (e.g., “A method of treating, ameliorating, or preventing cancer in a subject in need thereof, comprising providing the kit of claim 15 and administering to the subject gamitrinib from the kit according to the instruction manual in the kit.”
Patentable Weight
Under the printed matter doctrine, information claimed for its communicated content (e.g., such as dosing instructions, warnings, or usage guidelines) is generally not accorded patentable weight unless that information bears a functional or structural relationship to the physical substrate on which it is printed. Praxair Distribution, Inc. v. Praxair, Inc., IPR2015-00529 (PTAB July 7, 2016) recites, "If a limitation claims (a) printed matter that (b) is not functionally or structurally related to the physical substrate holding the printed matter, it does not lend any patentable weight to the patentability analysis . . . [and] may not be a basis for distinguishing prior art." The kit of claim 15 recites an instruction manual that merely informs the user about how to use the kit components (e.g., specifying a dosing regimen for a pharmaceutical composition).
Written dosing instructions are classic printed matter and are purely informational absent a functional relationship connoting a specific and integral structural characteristic (e.g., creates a functional relationship with drug container or formulation and gamitrinib) of the physical components (i.e., gamitrinib; see In re Nordt Dev. Co., 2018 WL 774097 (Fed. Cir. Feb. 8, 2018)). The instructions do not alter the structure or inherent function of the physical components (i.e., gamitrinib, wherein the drug itself determines its therapeutic properties) and the instructions do not impose a structural limitation (i.e., “administer from about 0.1-50 mg/kg per week” does not integrate any change to the composition, formulation, physical arrangement of the kit components nor originate a new and non-obvious functional relationship), thus the instruction manual limitation hold no patentable weight (see MPEP 2112.01(III) and King Pharmaceuticals, Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1279 (Fed. Cir. 2010)).
The kit instruction manual merely informs a user about an inherent property of a method of administering a drug at a certain dose with a statement of intended use for treating, ameliorating or preventing cancer in a subject in need thereof. Therefore, the instruction manual is disregarded and the claim is examined as if it read only "A kit comprising gamitrinib.", without the manual content.
The physical kit components (e.g., gamitrinib alone) are known from the prior art (Altieri and Kang, US-8466140-B2, published 18 June 2013) covering the core compound 17-demethoxy-17-((6-(triphenylphosphonio)hexyl)amino)geldanamycin containing a triphenylphosphonium tumor cell mitochondria targeting moiety (gamitrinib) and pharmaceutically acceptable salt thereof. Therefore, the prior art reference anticipate claim 15.
For the administration protocol to be accorded patentable weight that is not limited by printed matter doctrine, a separate method claim reciting active administration steps should be filed, rather than relying on instruction manual limitations in a kit claim.
Although administration is not within the literal scope of claim 15, in the interest of compact prosecution, the examiner has examined the claims as if administration of gamitrinib were incorporated in the dependent claims by way of an additional separate method of administration claim, serving as the new base claim. However, amendment to the claim set to include a new method of administration claim, incorporating by reference the kit of claim 15, is required to actually secure an interpretation of the dependent claims that includes administration of gamitrinib.
Claim Objections
Claims 15, 17, 22, 25, and 32 are objected to because of the following informalities:
Claim 15 recites, “A kit of treating” and should read “A kit for treating” (standard claim format). The applicant is advised to amend the claim accordingly.
Claim 17 recites, “treats, ameliorates and/or prevents”, which is inconsistent with claim 15 reciting, “treating, ameliorating, or preventing”. Claim 15 from which claim 17 depends does use “and/or” rather the terms are all used in the alternative. In addition, the verb form used is inconsistent. The applicant is advised to amend the claims to be consistent.
Claim 22 is objected to for the grammatical error, “instruction manual instruct administering…”, which uses the incorrect verb form. The applicant is advised to amend the claim to state, “instructs administering” or “instructs to administer”.
Claim 25 is objected to for the phrase, “A pharmaceutical formulation suitable for parenteral formulation...”, which contains redundant phrasing (“formulation” twice). The applicant is advised to amend the claim to state, “A pharmaceutical formulation suitable for parenteral administration” or “A pharmaceutical suitable for parenteral formulation”, but not both.
Claim 32 is objected to for the typographical error in the phrase, “The pharmaceutical composition claim 25...”, which is missing an “of”, creating an improper dependency. The applicant may overcome this objection by amending the claim to state, “The pharmaceutical composition of claim 25…”
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 Applicant regards as his invention.
Claims 18-21 and 25-33 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, regards as the invention.
Claim 18 recites, “the amount of Gamitrinib administered weekly to the subject is equal to or greater than the amount . . . during the standard dosing phase.” This is indefinite because an “acceleration dosing phase” that uses the same dose as the standard phase would not actually “accelerate” anything. While mathematically clear, the functional recitation (“acceleration”) is inconsistent with “equal to”, rendering the scope of the claim unclear. To overcome this rejection, the applicant is advised amend the claim to “greater than” only.
In claim 19, the “administration scheme” lacks antecedent basis. Claim 15 introduces “administration protocol” not “administration scheme.” The inconsistent terminology renders the claim indefinite because there is insufficient antecedent basis for this limitation in the claim. The applicant may overcome this rejection by amending the claim to replace “administration scheme” with “administration protocol”.
Similarly, the phrase, “the dosing phase” in claims 19-21 lacks explicit antecedent basis. The earlier claim language introduces “a drug dosing phase” (claim 15), therefore there is insufficient antecedent basis for this limitation in the claims, rendering the scope of the claims unclear. This may introduce ambiguity as to whether “dosing phase” is equivalent to the “drug dosing phase” or a broader concept. The applicant may overcome this rejection by amending the claims to add the missing “drug” modifier to “the dosing phase”.
Claim 20 is rejected as indefinite for claiming “at or below the no observed adverse effect level (NOAEL)” and “lower than the highest non-severely toxic dose (HNSTD)”. These are relative, study-dependent parameters that are not inherently fixed values, rather they incorporate by reference extrinsic standards, rendering the scope of the claim unclear. The specification ¶[0070] recites, “Referring to the “Example” section, the instant specification describes methods of determining the NOAEL, the HNSTD and the severely toxic dose…As such, one of ordinary skill in the art, reading in light of the instant specification, would be able to determine the NOAELs, HNSTDs and severely toxic doses of Gamitrinib in other mammalian subjects, without undue experimentation.” However, the NOAEL and HNSTD intended in claim 20 are still indefinite because they are not clearly tied to a specific species and study conditions or a recognized standard protocol.
The referenced Example section ¶[0174] of the specification provides a NOAEL and a severely toxic dose in 10% of the animals for Sprague-Dawley rats and ¶[0175] a NOAEL and HNSTD value for beagle dogs. The values are different, thus it would be unclear to one of skill in the art which values are intended to be used to establish the metes and bounds of claim 20, as the definition of NOAEL and HNSTD conflict per species. Further, the NOAEL and HNSTD terms are not defined in the context of human subjects and the precise method for determining these values in a human subject is not explicit, thus the values one may establish can vary and do not clearly establish the scope of the claim.
The applicant may overcome this rejection by amending the claims to state an explicit fixed amount of gamitrinib administered to the subject during the drug dosing phase (e.g., “The kit of claim 15, wherein the amount of Gamitrinib administered to the subject during the dosing phase is at or below a no observed adverse effect level (NOAEL) of 3.33 mg/kg/dose, or is lower than the highest non-severely toxic dose (HNSTD) of 6.25 mg/kg/dose.”, or better yet, “The kit of claim 15, wherein the amount of Gamitrinib administered to the subject during the dosing phase is at or below a 3.33 mg/kg/dose, or is lower than a 6.25 mg/kg/dose.”).
Likewise, claim 21 is rejected for claiming “Cmax … about 2000 ng/mL or less”. Cmax is a relative, study-dependent parameter that is not an inherently fixed values, rather incorporates by reference extrinsic standards, rendering the scope of the claim unclear. The Cmax value of claim 21 is not clearly tied to a specific species and study conditions or a recognized standard protocol and also depends on assay method and sampling time. Cmax is indefinite without provision of explicit pharmacokinetic measurement conditions in the specification, in context of the intended subject species (e.g., human). In the Example section of the specification Cmax measurements are reported for Sprague-Dawley rats and beagle dogs (¶[0174] and ¶[0175], respectively). The precise method for determining Cmax values in a different species of subject (e.g., human) is not explicit and would vary under different experimental conditions. The applicant may overcome this rejection by amending the specification to state an explicit fixed protocol for determining gamitrinib Cmax in the intended subject (e.g., human) during the drug dosing phase.
Claim 21 also lacks proper antecedent basis for “the maximum serum concentration (Cmax)”, in which Cmax has not been previously introduced in the claim from which it depends (claim 15). To overcome this rejection, the applicant is advised amend the claim to change “the maximum serum concentration (Cmax)” to “a maximum serum concentration (Cmax)”.
Claims 25 and 26 are rejected as indefinite for reciting "lecithin (Lipoid S100)". The term "Lipoid S100" is a trademarked commercial product (a highly purified soy lecithin containing ≥94% phosphatidylcholine, manufactured by Lipoid GmbH). While the specification mentions Lipoid S100 (¶[0153]), it does not provide the structural composition of this product in terms of, for example, the percentage of phosphatidylcholine, the fatty acid composition, or other defining characteristics. The generic term "lecithin" appears elsewhere (¶[0045]–[0047]), but the claim specifically recites "lecithin (Lipoid S100)," which creates uncertainty as to whether the claim is limited to that specific product. A person of ordinary skill in the art would not know with reasonable certainty whether the claim is limited to the specific Lipoid S100 product, or whether any lecithin falls within the claim, or what the essential characteristics of the lecithin must be.
Trademarked products may change composition over time (e.g., formulation changes by the manufacturer) or may have batch-to-batch variability, and the claim does not define the structural or compositional limitations of the lecithin component, thus the scope of what is encompassed as Lipoid S100 is not fixed therefore the scope of the claim could shift with the commercial product. Claims must define the invention in terms of essential structural characteristics, composition, or function, not by trade name alone (see MPEP § 2173.05(u)). To overcome this rejection, the applicant is advised yo amend the claims to recite lecithin in terms of structural or compositional limitations (e.g., "lecithin comprising at least 90% phosphatidylcholine" or as otherwise supported by the specification), remove the trademark and rely on the generic term "lecithin", or define the trademarked product in structural terms (e.g., "lecithin comprising at least 94% phosphatidylcholine") in the specification. Dependent claims 27-33 are included in this rejection because they do not cure the defect noted above.
Claims 27 and 28 are rejected as indefinite for failing to specify the weight basis for the percentage concentrations (e.g., weight or volume) and the basis of the percent (e.g., based on the weight or volume of the total composition), rendering the scope of the claims ambiguous. Where a claim recites percentages without specifying the basis for the percentages (e.g., by weight or by volume of the total composition), the claim considered indefinite (see MPEP § 2173.05(b)).
Claims 27 and 28 recite a pharmaceutical composition comprising various components with concentrations expressed in both "mg/mL" and "%". The claim does not specify whether the percentages are by weight/volume (w/v), weight/weight (w/w), or volume/volume (v/v) based on the total weight or volume of the composition. Different components might logically be measured on different bases. For example, it is unclear whether "about 0.5-15% DMSO" means 0.5-15 grams of DMSO per 100 mL of composition (w/v), 0.5-15 grams per 100 grams of composition (w/w), or 0.5-15 mL per 100 mL of composition (v/v). These different bases yield different concentrations that are distinct and non-interchangeable measurements and, therefore, different claim scopes. The presence of "mg/mL" for the gamitrinib component indicates that the composition is a liquid, but it does not conclusively establish the basis for the percentages of the other components. Thus, the context does not resolve the ambiguity.
While the specification at ¶[0054] and ¶[0153] provides an exemplary formulation with "about 2.5% DMSO" in the context of a specific manufacturing process, it does not explicitly state whether the percentages are w/v, w/w, or v/v of the total composition. Moreover, a claim's scope is not limited to the examples (see In re Vamco Mach. & Tool, Inc., 752 F.2d 1564, 1577 (Fed. Cir. 1985), wherein the claims define the invention, not the examples). A person of ordinary skill in the art would not know with reasonable certainty which basis is intended. To overcome this rejection, the applicant is advised to amend the claims to specify the basis for the percentages (e.g., by changing "%" to "% w/v," "% w/w," or "% v/v" of the total composition).
Claim 29 is rejected as indefinite for claiming “a solution of a suspension”, which is internally inconsistent and technically unclear. A composition cannot simultaneously be a solution (i.e., a homogenous mixture wherein the solute is completely dissolved) and a suspension (i.e., a heterogenous mixture where solid particles are dispersed but not dissolved), thus rendering the scope of the claim nonsensical. One of ordinary skill in the art would not understand what physical form is being claimed. To overcome this rejection, the applicant may amend the claim to state, “a solution or a suspension” (which appears to be the intend based on the specification ¶[0122], however ¶[0055] and ¶[0057] of the specification recites “a solution of a suspension” as in the claim language, whereas throughout the examples in the specification, the formulation is consistently referred to as a suspension not a solution) or specify the emulsion/dispersion if intended.
Claims 30-33 are rejected for claiming particle size with measurement ambiguity (i.e., DLS vs laser diffraction vs microscopy). The “average particle size” and “D(0.9) size” are undefined and are indefinite without the provision of specifying the measurement technique in the specification. Claims 32 and 33 are also rejected as indefinite for “D(0.9) size”, which is unclear terminology without definition in the specification. The standard phrasing would be “D90 particle size” or “particle size distribution D(0.9)”. To overcome this rejection, the applicant may amend the claim to state “D90 particle size” or “particle size distribution D(0.9)” or amend the specification to explicitly define “D(0.9) size”.
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 15-17, 20-25 and 29 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Zhang et al. (US-20180228740-A1; published 16 August 2018, hereinafter referred to as “Zhang”).
Zhang teaches kits comprising gamitrinib, containing instructions on dosing ¶[0094]-[0095] and optionally contains instructions for administration to a subject ¶[0096] and ¶[0101] including administration comprising drug dosing phase of weekly administration ¶[0096], wherein a method of treating cancer comprising administering gamitrinib (claims 4 and 5) administered at a dosage of 0.1-50 mg/kg (claim 6) per body weight ¶[0085], encompassing the limitations of instant claim 15. The term cancer includes tumors, Hodgkin's and non-Hodgkin's lymphoma and in one embodiment, the cancer is a melanoma (a solid tumor form) ¶[0043], encompassing the limitation of instant claim 16.
The examples at ¶[0233] teach the use of gamitrinib (15 mg/kg) alone or in combination with a MAPK inhibitor (at two doses, 5 and 15 mg/kg). Further, both ¶[0111] and ¶[0112] explicitly state embodiments of the invention include administration of gamitrinib alone, wherein administration is used to treat resistant cancers (claim 16), thus teaching the limitation of instant claim 17.
Zhang teaches that “The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.” (¶[0087]), wherein the NOAEL (No Observed Adverse Effect Level) is the highest exposure level of a substance at which no biologically or statistically significant adverse effects are observed in the test population, thus Zhang integrally teaches the limitation of instant claim 20 of being at or below the NOAEL. Zhang also emphasizes targeting compounds which exhibit high therapeutic indices (the dose ratio between toxic and therapeutic effects, or LD50 (the dose lethal to 50% of the population)/ED50 (the dose therapeutically effective in 50% of the population) (¶[0086]), meaning the effective dose is much higher than the toxic dose and there is a large gap between the two. This implicitly requires that the administration dose is well below severely toxic levels (e.g., the LD50). Further, evidentiary reference by Altieri (Altieri, Clinical Development of Gamitrinib, a Novel Mitochondrial Targeted Small Molecule Hsp90 Inhibitor, Annual US Army Medical Research and Material Command Report, Award Number: W81XWH-13-100193, Sep 2016), established that a gamitrinib dose of 5 mg/kg was considered the NOAEL (page 5, last two lines), which is innately lower than the highest non-severely toxic dose. Zhang establishes acceptable dose ranges as an effective amount of about 0.001 mg/kg to 1000 mg/kg body weight and in another embodiment, the effective amount is less than about 5 g/kg, emphasizing the effective amount can be determined by the attending physician and depends on the condition treated, the route of delivery, age, weight, severity of the patient's symptoms and response pattern of the patient (¶[0085]). The example embodiments by Zhang include a dose of 5 mg/kg gamitrinib (¶[0233]-[0234]). Thus, the limitation of instant claim 20 is taught by Zhang.
Based on the pharmacokinetic profile of gamitrinib in evidentiary reference by Hayat et al. (Hayat et al., Feasibility and safety of targeting mitochondria for cancer therapy - preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor. Cancer Biol Ther. 2022 Dec 31;23(1):117-126; published online 06 February 2022), establishing a mean half-life (t1/2) of 12.2 ± 1.55 h, a mean area under the curve from initial to last measurable concentration (AUC0-t) value of 783.199 h∙ng/mL and mean area under the curve from time zero extrapolated to infinite time (AUCINF) value of 976.002 h∙ng/mL, a mean clearance (CL) value of 85.656 ± 5.856 ml/min/kg and a mean volume of distribution at steady state (Vss) value of 65.471 L/kg, a mean gamitrinib Cmax of 1175.807 ng/mL results after the administration of 5 mg/kg (page 4, PK studies paragraph), therefore the dosing phase dose of 5 mg/kg gamitrinib or lower taught by Zhang intrinsically meets the limitation of instant claim 21 of a Cmax value about 2000 ng/mL or less.
Zhang teaches kits comprising containing gamitrinib and a MAPK inhibitor including administration instructions (¶[0094]-[0102]), wherein MAPK is involved in pro-inflammatory biological responses (¶[0053]), thus the kit comprising gamitrinib and a MAPK inhibitor taught by Zhang integrally encompasses the limitation of instant claim 22, wherein the kit comprises and anti-inflammatory compound. As further evidence, Zhang teaches wherein the MAPK inhibitor is vemurafenib (claim 4; and the preclinical analog PLX4720), evidentiary reference by Eder et al. (Eder et al., Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis. Blood Adv. 2022 Feb 8;6(3):970-975), confirms vemurafenib inhibits systemic inflammation and rapidly improves the clinical picture (page 1, Key Points). In addition, other MAPK inhibitors known in the art, primarily targeting the p38 MAPK and JNK signaling pathways function as anti-inflammatory and/or renal protective compounds (e.g., SB203580, SP600125, selonsertib, VX-702, VX-745, doramapimod, fisetin, salvianolic acid, ginsenosides, berberine, curcumin, liquiritigenin, baicalin, etc.).
Zhang teaches wherein the compositions comprising gamitrinib with parenteral routes of administration (¶[0069]), parenteral preparations including solutions or suspension formulations (¶[0070]), and wherein in one embodiment, the subject of these methods and compositions is a human (¶[0042]), thus directly teaching the limitations of instant claims 23, 24 and 29.
Zhang teaches wherein solutions or suspensions are used for parenteral application and can include water, other solvents, and tonicity adjusting agents such as dextrose (¶[0070]). In addition, a carrier solvent explicitly including water, sugars (which would include sucrose and dextrose), lecithin, and surfactants (which would include polysorbate 80) (¶[0071]) are also suitable for the invention of Zhang. DMSO is also explicitly taught as a suitable carrier for administration in ¶[0083] by Zhang. Surfactants and emulsifiers (which would include polysorbate 80), sucrose, and solubilizer and stabilizer are also are also noted as pharmaceutically compatible binding agents, and/or adjuvant materials that can be included as part of the composition (¶[0075]). Thus, the limitation of claim 25 is explicitly taught by Zhang and the limitation of instant claim 26 is encompassed within the teachings of Zhang but is not explicitly taught. Zhang does not explicitly recite the specific formulation and concentration limitations of instant claims 26-28, nor the particle size limitations of instant claims 30-33.
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.
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 15, 18 and 19 are rejected under 35 U.S.C. § 103 as being unpatentable over Zhang et al. (US-20180228740-A1; published 16 August 2018, hereinafter referred to as “Zhang”).
Zhang directly teaches the limitation of instant claim 15, as described above, from which instant claims 18 and 19 depend, however does not explicitly teach the acceleration dosing phase and recovery phase limitations of instant claims 18 and 19.
Zhang teaches the use of a higher initial dose followed by lower maintenance doses, as well as periodic discontinuous administration regimens. Zhang explicitly discloses, “In one embodiment, the first dose of the composition is higher than the subsequent doses.” (¶[0083]), thus fundamentally teaching an acceleration dosing phase (higher initial dose) followed by a standard dosing phase (lower subsequent doses). Zhang’s disclosure of a first dose “higher than” subsequent doses encompass the instant claimed “greater than” limitation, wherein Zhang’s teachings also extend to encompass the “equal to” limitation of the instant claim of merely using the same dose throughout a dosing regimen. Zhang further discloses that administration may be repeated periodically (¶[0069] and ¶[0108]), and that kits may be organized to indicate formulations to be taken at desired times (i.e., kits with dosing schedules; ¶[0094]).
Zhang also teaches periodic discontinuous administration, the use of placebos during periods when the composition is not delivered, and the concept of repeating administration periodically, consistent with the “recovery phase” recited in instant claim 19, where the subject is not administered the drug. Zhang recites, “When the composition is to be delivered periodically in a discontinuous fashion, a package or kit can include placebos during periods when the composition is not delivered.” (¶[0096]). This clearly teaches a phase during which the composition is not delivered (i.e., a recovery or drug-free period). Zhang also teaches that administration may be “repeated periodically” (¶[0069] and ¶[0108]) and that dosages may be administered “continuously for a certain period of time, or periodically every week, month, or quarter” (¶[0108]), hence, repeated periodic administration, which characteristically would include intervals between administrations where no drug is administered.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to interpret the teachings of Zhang to include the instant claimed features of an acceleration dosing phase (higher or equal initial dose) and a recovery phase (drug-free period), which are also well-known and routine aspects of pharmaceutical dosing regimens. The instant claimed acceleration dosing phase followed by a standard dosing phase is squarely taught by the prior art, and any minor variations are within the skill of the art. One of ordinary skill in the art would have recognized that a dosing regimen comprising an initial higher dose (an “acceleration” or “loading” phase) followed by a lower maintenance dose is a routine and well-established pharmacokinetic strategy to rapidly achieve therapeutic drug levels while minimizing cumulative toxicity.
Zhang’s express teaching of including placebos during periods when the composition is not delivered (¶[0096]) confirms that such drug-free intervals are a routine feature of the disclosed kits. One of ordinary skill in the art would understand that in a periodic discontinuous dosing regimen, the periods between administrations serve as a recovery phase, allow the subject to recover from any potential adverse effects before the next dose. Therefore, Zhang teaches the limitations of instant claims 18 and 19. No unexpected results or criticality have been demonstrated by applicant that would render these otherwise obvious features patentable.
Claims 25-28 and 30-33 are rejected under 35 U.S.C. § 103 as being unpatentable over Zhang et al. (US-20180228740-A1; published 16 August 2018, hereinafter referred to as “Zhang”) in view of Singh (US-20020037877-A1; published 28 March 2002) and Betageri et al. (WO-2012058668-A2; published 03 May 2015, hereinafter referred to as “Betageri”).
Zhang teaches the limitation of instant claim 25, as described above, from which instant claims 26-28 and 30-33 depend, however does not explicitly teach the specific formulation and concentration limitations of instant claims 26-28 and the specific particle size limitations of instant claims 30-33.
Zhang teaches parenteral formulations comprising water, DMSO, polysorbate 80, lecithin, sucrose, and dextrose individually, though not necessarily in combination. Specifically, Zhang discloses solutions or suspensions for parenteral application including water, other solvents, and tonicity adjusting agents such as dextrose (¶[0070]), carrier solvents including water, sugars (which would include sucrose and dextrose), lecithin, and surfactants (which would include polysorbate 80) (¶[0071]), DMSO as a suitable carrier for administration (¶[0083]), and surfactants (including polysorbate 80), sucrose, and solubilizers as pharmaceutically compatible adjuvants (¶[0075]). Zhang does not explicitly recite the specific formulation and concentration limitations of instant claims 26-28, nor the specific particle size limitations of instant claims 30-33.
Singh teaches stable aqueous pharmaceutical suspension compositions containing a water-insoluble drug compound and lecithin as a stabilizing additive (claim 1), wherein the water-insoluble drug compound is present in an amount from about 0.001-5% (claim 2; encompassing a 0.1-2.5% (w/v) or 0.5% (w/v) concentration gamitrinib), the lecithin is present in an amount from about 0.01-2% (claim 7; encompassing 0.01-1% and 0.031%), surfactant including polysorbate 80 (claim 10) is present in an amount from about 0.01-2% (claim 11; encompassing 0.025-1% and 0.125%), and further comprising one or more excipients selected from tonicity-adjusting agents (e.g., dextrose and sucrose) (claim 12), wherein the tonicity-adjusting agent is present in an amount sufficient to cause the final composition to have an osmolality generally about 150-450 mOsm/L, and if desired or required also contain one or more conventional excipients (¶[0021]; DMSO is a conventional excipient used as a cosolvent to solubilize poorly soluble drugs in water). Water is also used in example formulations (page 4, Table 1). Singh also teaches that micronized drug particles having an average particle size ≦10 μm [10,000 nm] (based on surface area (dsn)) are preferred, wherein sizing techniques, such as ball milling or micronizing, can be used to adjust the particle size into the desired range (¶[0017] and ¶[0025]). The primarily type of lecithin is phosphatidylcholine but can include phosphatidylglycerol, phosphatidylinositol, sphingomyelin, and phosphatidylethanolamine and lecithin derivatives distearoylphosphatidyl choline, dipalmitoylphosphatidyl choline, and dimirystoylphosphatidyl choline (¶[0018]; preferably lecithin is ≥75% phosphatidylcholine). Singh does not explicitly teach the use of the specific tonicity-adjusting agent sucrose at 0.5-10% or 1.25% or dextrose at 1-15% or 4.375% or the inclusion of DMSO at about 0.5-15% or about 2.5%. Singh also does not explicitly teach an average particle size of about 50-500 nm or about 154 nm or a D(0.9) size of about 50-1000 nm or about 229 nm.
Betageri teaches free-flowing powder formulations comprising a phospholipid (lecithin), a poorly water-soluble drug substance (such as gamitrinib), a surfactant (including polysorbate 80), and solubilizing aids including sucrose and glucose (dextrose) (claims 1-6), with DMSO as a water-miscible solvent (claim 13). Betageri teaches the following overlapping ranges with instant claim 27 and the specific ratios and ranges that encompass the exact values recited in claim 28:
Drug substance amount from about 0.01-50% by weight, specifically 0.1%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 1.75%, 2%, 3% (¶[029]), which encompasses the instant claimed 1-25 mg/mL (approximately 0.1-2.5% w/v) range. Drug substance amount of 0.5% (¶[029]) corresponds to about 5 mg/mL.
Drug substance to phospholipid (lecithin) ratio from 1:0.1 to 1:100 (w/w) (¶[030]), which, for a drug concentration of 0.1-2.5%, yields a lecithin range of 0.01-97.5%, encompassing the instant claimed 0.01-1% lecithin, including 0.031% lecithin for a 5 mg/mL drug concentration.
Surfactant to lipid ratio from 1:0.1 to 1:50 (¶[033]), which, for the instant claimed lecithin range, yields a surfactant range encompassing the instant claimed 0.025-1% polysorbate 80 and includes 0.125% polysorbate 80 for the recited lecithin amount.
Solubilizing aid (sucrose or glucose) from about 1-90% of the total weight of the solid content (¶[042]), which encompasses the instant claimed 0.5-10% sucrose and 1-15% dextrose and 1.25% sucrose and 4.375% dextrose.
Water-miscible solvent (e.g., DMSO) comprises about 1-90% (v/v) of the total liquid content (¶[045]), wherein under the broadest reasonable interpretation, having “about” defined as ±20% (¶[0020] of the instant specification), the instant claimed 0.5-15% DMSO extensively overlaps with the 1-90% range taught by Betageri and squarely encompasses the instant claim 28 recited 2.5% DMSO.
To the extent the claimed lower limit of 0.5% DMSO extends slightly below the 1% lower limit taught by Betageri (based on the 1-90% solvent range), such a modest extension would be obvious (see In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990), wherein selecting a slightly narrower or broader range from a prior art range is prima facie obvious absent a showing of criticality). Further, the instant specification provides only working examples at 2.5% DMSO and no data demonstrating the lower 0.5% DMSO limit, which appear to be arbitrary. Merely extending the range downward by 0.5% is a routine optimization that would have been obvious to try (see KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), wherein obviousness may be shown where a skilled artisan would have had a reasonable expectation of success in trying a predictable variation).
One of ordinary skill in the art would have been motivated to combine these teachings of Zhang, Singh, and Betageri to arrive at the specific combination of excipients recited in claims 26-28. Each component is well-known in the art for its respective function, wherein DMSO is as a known and widely used co-solvent, polysorbate 80 is as a known and widely used surfactant, lecithin is a known and widely used stabilizer/emulsifier, and sucrose and dextrose are known and widely used tonicity adjusters or cryoprotectants. Combining these known excipients to formulate a parenteral drug product does not constitute an inventive step but rather the application of routine pharmaceutical formulation principles (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007), wherein the combination of familiar elements according to known methods is likely obvious when it does no more than yield predictable results).
In addition, the instant claimed ranges substantially overlap with the ranges or ratios explicitly taught by Singh and/or Betageri and most are fully encompassed by the broader ranges or ratios taught in Betageri. Where a claimed range falls within a broader prior art range, a prima facie case of obviousness exists (see In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003), wherein when the prior art discloses a range that overlaps with or is broader than the claimed range, a prima facie case of obviousness exists, and In re Harris, 409 F.3d 1339, 1342 (Fed. Cir. 2005)).
Choosing the specific formulation and ranges of the instant claims is merely a routine selection as a matter of routine experimental optimization within the art of specific known excipients and values from within the ranges taught by Betageri (see In re Aller, 220 F.2d 454 (CCPA 1955) and In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003), where 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). The combination of the known excipients sucrose and dextrose are taught by Betageri as being suitable for the invention as they are well-known and routinely used solubilizing aids and tonicity adjusters in the art. Moreover, the selection of a particular point within a disclosed range, without any showing of unexpected results or criticality is also obvious (see In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003), wherein selecting a specific value from within a prior art range is prima facie obvious).
The prior art teachings of Zhang, Singh, and Betageri provide a roadmap for arriving at the instant claimed formulations, and no evidence has been presented that this specific combination yields unexpected results compared to the prior art. Therefore, rendering instant claims 26-28 obvious as routine and obvious optimizations of the teachings of Zhang in view of Singh and Betageri.
Betageri teaches that dispersed particles of the formulation are nanoparticles having mean diameters from about 100-500 nm (¶[058]), encompassing the instant claim 31 average particle size of about 154 nm. No evidence has been provided that a particle size of 154 nm yields any unexpected property compared to other particle sizes within the 100-500 nm range. Selecting a single, non-critical value from within a disclosed range is prima facie obvious (see In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Therefore, instant claim 31 is obvious over Betageri in view of the teachings of Zhang and Singh.
Under the broadest reasonable interpretation, wherein “about” is defined as ±20% (¶[0020] of the instant specification), the claimed range extends to an approximately 80 nm lower limit. This range also substantially overlaps with the instant claim 30 range of about 50-500 nm. To the extent the claimed lower limit of 50 nm extends slightly below Betageri’s 100 nm lower limit, such a modest extension is an obvious to one of skill in the art (see In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990), wherein selecting a slightly narrower or broader range from a prior art range is prima facie obvious absent a showing of criticality). Further, the instant specification provides only working examples having average particle sizes ranging from 197-225 nm (Table 1-1), which falls squarely within Betageri’s 100-500 nm range. No data has been presented demonstrating the 50-100 nm subrange for the instant invention, let alone a demonstration on unexpected results at the 50-100 nm subrange, in fact, the lower limit of the instant claimed range appears to be arbitrary.
A prima facie case of obviousness arises when a claimed range overlaps with or falls within a prior art range (see In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Merely extending the lower limit of a known particle size range by 50 nm is a routine optimization that a person of ordinary skill in the art would have found obvious to try, with a reasonable expectation of success (see KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), wherein obviousness may be shown where a skilled artisan would have had a reasonable expectation of success in trying a predictable variation). Therefore, instant claim 30 is also obvious over Betageri in view of the teachings of Zhang and Singh.
Betageri teaches that diameters of the particles are generally from about 100-900 nm (¶[058]). Under the broadest reasonable interpretation, wherein “about” is defined as ±20% (¶[0020] of the instant specification), this range would extend to the upper limit of 1080 nm. The modest extension to 50 nm at the lower end and 1000 nm at the upper end (compared to 100 nm and 900 nm) represents a routine optimization that would have been obvious to a person of ordinary skill in the art (see In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990)). The D(0.9) particle size of about 50-1000 nm of instant claim 32, thus overlaps substantially with the overall particle range (which includes the D(0.9) range) taught by Betageri and the 50 nm lower limit extension is rendered obvious to try. The instant claim 33 specific value of about 229 nm, falls squarely within the overall particle size range taught by Betageri. Selection of this specific value does not represent a critical or unexpected selection. No evidence has been provided that a D(0.9) size of 229 nm yields any unexpected property compared to other particle sizes within the 100-900 nm range. Thus, selecting a similar overlapping range and a single, non-critical value from within a disclosed range is prima facie obvious (see In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Therefore, instant claims 32 and 33 are obvious over Betageri in view of the teachings of Zhang and Singh.
In summary, the instant claimed formulations and particle size parameters in claims 26-28 and 30-33 are either explicitly taught, encompassed by broader ranges, or represent routine selections from the prior art. The combination of known excipients (e.g., DMSO, polysorbate 80, lecithin, sucrose, dextrose) to formulate a poorly water-soluble drug is a predictable application of standard pharmaceutical formulation principles. The instant claimed ranges and specific values are either fully within or only modest extensions of prior art ranges, and no unexpected results or criticality have been demonstrated. Accordingly, claims 26-28 and 30-33 are rejected as obvious over the cited prior art.
Claim Rejections – Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
Conclusion
No claims are allowed.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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