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
Amendments to the Claims and Arguments/Remarks filed 08 September 2026, in response to the Office Correspondence dated 08 April 2026, are acknowledged.
The listing of Claims filed 08 September 2026, are under examination. Claims 15-25, and 27-29 are pending. Claims 15, 17-22, 25, and 27-29 are amended, claims 26 and 30-33 are canceled, claims 1-14 and 34-38 remain withdrawn from consideration, and no new claims have been added.
Response to Amendment
The amendments are entered. Claim 15 now requires a pharmaceutical formulation comprising Gamitrinib, water, DMSO, polysorbate 80, lecithin, sucrose, and dextrose, and an instruction manual reciting a standard dosing phase of about 50 mg to about 800 mg Gamitrinib per week. Claim 25 requires the same seven formulation components. Claims 27 and 28 identify the concentration bases. Claim 29 recites a “solution or a suspension.”
The applicant’s amendments to claims 15, 17, 22, and 25 correct the grammatical and formal defects. Those objections are withdrawn. The objection to claim 32 is moot because claim 32 is canceled.
Claim 18 now requires the acceleration dosing phase amount to be “greater than” the standard dosing phase amount. Claim 19 consistently recites “administration protocol,” and claims 19-21 refer to “the drug dosing phase.” Claim 20 replaces relative NOAEL/HNSTD terminology with numerical limits of 3.33 mg/kg/dose and 6.25 mg/kg/dose. These amendments cure the prior indefiniteness and antecedent-basis defects. The § 112(b) rejections of claims 18-20 on those grounds are withdrawn.
Claim 21 now recites “a maximum serum concentration (Cmax)” and an upper value of about 1400 ng/mL. The applicant argues Examples 2-4 provide a Cmax determination protocol. The examiner does not fully agree that the cited disclosure establishes a single fixed human pharmacokinetic protocol for every Cmax determination. On reconsideration, however, in light of the specification and the ordinary meaning of Cmax to a person of ordinary skill in pharmacology, the record no longer establishes that the skilled artisan would be unable to determine the limitation’s scope with reasonable certainty. The prior § 112(b) rejection of claim 21, including the antecedent-basis ground, is withdrawn.
Claim 25 now recites “lecithin” instead of “Lipoid S100.” Claims 27 and 28 now state concentration bases, including v/v for DMSO and w/v for polysorbate 80, lecithin, sucrose, and dextrose. Claim 29 now recites that the formulation “is a solution or a suspension.” The corresponding § 112(b) rejections are withdrawn. The § 112(b) rejections directed to canceled claims 26 and 30-33 are moot.
Claim 15 remains construed as a kit claim, not a method-of-treatment claim. Claim 15 requires a physical pharmaceutical formulation and an instruction manual. The manual’s instructions communicate information about use. They do not require actual administration of Gamitrinib to a subject. Printed-matter limitations are not ignored. All limitations are considered. But once a limitation is determined to claim informational content, that content is not accorded patentable weight absent a new and unobvious functional relationship with its physical substrate (see MPEP § 2111.05; In re Ngai, 367 F.3d 1336, 1339 (Fed. Cir. 2004)). Instructions accompanying physical chemicals do not acquire patentable weight merely by telling the user how to employ those chemicals.
Here, the dosing information does not change the structure or composition of Gamitrinib, the formulation, or the manual, and it creates no new functional relationship with the physical substrate. The communicated dosing information is therefore not accorded patentable weight in distinguishing the physical kit from the prior art. Similarly, dependent claims 18-21 do not patentably distinguish the physical kit merely by further defining administration information.
The applicant argues amended claim 25 is not anticipated by Zhang because claim 25 now requires Gamitrinib, water, DMSO, polysorbate 80, lecithin, sucrose, and dextrose in combination. This argument is persuasive. Anticipation requires every limitation in a single reference, arranged as required by the claim. Zhang does not expressly disclose the specific combination now required by claim 25, including polysorbate 80, lecithin, sucrose, and dextrose together with Gamitrinib, water, and DMSO. Accordingly, the prior anticipation rejection cannot be sustained by selecting separate ingredients from different generic disclosures in Zhang and retrospectively assembling the claimed formulation and the § 102 rejection of claims 15-17, 20-25 and 29 are rejected under 35 U.S.C. § 102(a)(1) over Zhang is withdrawn.
The prior § 103 rejection of claims 15, 18, and 19 over Zhang alone is no longer sufficient because amended claim 15 now contains the seven-component physical formulation limitation. That Zhang-alone rejection is withdrawn as stated, however, the applicant’s amendment necessitates application of the Zhang, in view of Singh and Betageri combination to the newly added formulation limitation of claim 15, and the claims are rejected as such, as detailed in the new rejection below.
With regards to the prior § 103 rejection of claims 25-28 and 30-33, the applicants arguments with respect to the various Singh and Betageri numerical ranges as directly overlapping with the amended concentration limitations, given the now specified v/v or w/v limitations of amended claims 27 and 28, is persuasive and the reasoning is not maintained in its prior form. New rejections have been outlined, as detailed below. The § 103 rejection of claim 29, depending from amended claim 25, is withdrawn as previously stated and is re-entered on the revised combination stated below.
The new § 103 combination, detailed below, against amended claim 15 and claims incorporating its newly added formulation limitations, the new ground was necessitated by the applicant’s amendment of the independent claim. A dependent claim is treated as amended for finality purposes when the independent claim from which it depends is amended because the dependent claim incorporates the amended subject matter. The new objections and rejections results from the applicant’s amendment.
The applicant requests clarification because the prior Office Correspondence contained general language about nonstatutory obviousness-type double patenting but did not identify a reference patent or application, identify reference claims, or state that particular application claims were rejected over particular reference claims. The generic explanatory paragraph was a drafting error. Accordingly, no nonstatutory double-patenting rejection from the prior Office Correspondence is outstanding and the prior informational/explanatory section has been properly deleted from this Office Correspondence.
New Objections and Rejections
The following new rejections are made from the previous Office Correspondence dated 08 April 2026, as the applicant's amendment necessitated the new grounds of rejection presented below based on the amended/newly cited limitations.
Claim Objections
Claims 15 and 20 are objected to because of the following informalities:
Claim 15 is objected to because the punctuation and organization of the nested “comprising” clauses create an avoidable grammatical ambiguity as to whether the “instruction manual” is a separate component of the kit or is included within the recited pharmaceutical formulation. Claim 15 presently recites, in relevant part, “the kit comprising: a pharmaceutical formulation suitable for parenteral administration, wherein the formulation comprises: Gamitrinib … water, dimethyl sulfoxide (DMSO), polysorbate 80, lecithin, sucrose, and dextrose, and an instruction manual …”.
The intended hierarchy appears from the context to be that the kit contains both (1) the pharmaceutical formulation and (2) the instruction manual. The claim should therefore be amended, for example, by replacing the comma following “dextrose” with a semicolon (e.g., “… polysorbate 80, lecithin, sucrose, and dextrose; and an instruction manual …”). This is treated as a matter of claim form, because the intended construction is reasonably ascertainable from the claim as a whole. Appropriate correction is required. Applicant is reminded that the instruction manual has no patentable weight as it is printed matter.
Claim 20 contains the grammatically awkward expressions “at or below a 3.33 mg/kg/dose” and “lower than a 6.25 mg/kg/dose.” The articles “a” should be deleted or the limitation should be rewritten in terms of “a dose of,” e.g., “at or below 3.33 mg/kg/dose” or “at or below a dose of 3.33 mg/kg.” The claim additionally recites overlapping alternatives because every value at or below 3.33 mg/kg/dose also falls below 6.25 mg/kg/dose. That redundancy does not, standing alone, render the claim indefinite. The outer scope of the disjunctive numerical limitation is ascertainable, therefore, no new rejection of claim 20 under 35 U.S.C. 112(b) is made on this basis.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. § 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 15-24 are rejected under 35 U.S.C. 112(a) because the specification as originally filed does not reasonably convey to one of ordinary skill in the art that the inventor had possession of the subject matter now claimed, specifically the administration protocol of amended independent claim 15 in which the standard dosing phase administers Gamitrinib at a fixed weekly amount ranging from about 50 mg to about 800 mg per week.
The pertinent inquiry is whether the disclosure as originally filed reasonably conveys to a person of ordinary skill in the art that the inventor had possession of the claimed subject matter as of the filing date (see Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc); MPEP §2163). Each limitation of an amended claim must be expressly, implicitly, or inherently supported by the application as originally filed. Where separately disclosed limitations are subsequently combined, the relevant question is whether the original disclosure reasonably conveyed possession of the claimed combination, rather than merely whether each component of that combination can independently be located somewhere in the disclosure (see Hyatt v. Dudas, 492 F.3d 1365, 1371 (Fed. Cir. 2007)).
Here, the application provides several materially different dosing disclosures. First, the disclosure expressly associates the “standard dosing phase” with weight-normalized weekly dosing. In the standard dosing phase, Gamitrinib is disclosed at about 0.05 mg/kg/week to about 50 mg/kg/week, including numerous narrower ranges and individual weight-normalized weekly doses. Second, when the originally filed claims expressly recite a fixed human weekly dose in the standard dosing phase, original claims 11 and 12 recite approximately 5 mg/week to 100 mg/week, including individual values from approximately 5 through 100 mg/week. Third, elsewhere in the specification, in a general discussion of amounts of compounds “for administration,” the disclosure includes among numerous nested dosage ranges “about 50 mg to about 800 mg.” That passage does not identify the 50-800 mg range as a dose used during the standard dosing phase and does not itself characterize that range as an amount administered per week.
Thus, the application expressly discloses a standard dosing phase using weight-normalized weekly amounts extending to 50 mg/kg/week; a human fixed-dose standard dosing phase of approximately 5-100 mg/week; and separately, a generic compound-administration amount of approximately 50-800 mg. What the application does not expressly disclose is the combination now required by claim 15 of approximately 50-800 mg administered weekly during the standard dosing phase.
The issue is therefore not that the numerical endpoints 50 mg and 800 mg are wholly absent from the original disclosure. Rather, the issue is whether the application reasonably conveyed that the inventors regarded the specifically claimed 50-800 mg range as the fixed weekly dose range for the standard dosing phase. The present record does not identify language connecting the generic 50-800 mg administration range to the standard dosing phase. When the application expressly identifies a fixed-dose human standard-phase range, it identifies the materially narrower approximately 5-100 mg/week range.
The Federal Circuit has cautioned that written-description support cannot be established merely by retrospectively assembling separately disclosed numerical values or embodiments into a claimed range that the disclosure itself did not reasonably identify (see Indivior UK Ltd. v. Dr. Reddy’s Laboratories S.A., 18 F.4th 1323, 1328-30 (Fed. Cir. 2021)). The disclosure must provide sufficient information from which the claimed numerical subject matter is reasonably discernible rather than reconstructed after the fact. The determination is based on the particular disclosure here wherein the specification separately and expressly identifies the standard dosing phase, expressly supplies standard-phase weekly dose ranges, and, for fixed-dose human standard dosing, supplies an approximately 5-100 mg/week range, but does not identify the separately listed generic 50-800 mg administration range as a standard-phase weekly regimen.
Accordingly, the application as originally filed does not presently reasonably convey possession of the amended limitation requiring a standard dosing phase “during which the amount of Gamitrinib administered weekly to the subject ranges from about 50 mg to about 800 mg.” Claims 16-24 depend from claim 15 and therefore incorporate the unsupported limitation and are rejected for the same reason. The applicant may traverse this rejection by identifying where the application as originally filed expressly, implicitly, or inherently conveys to one of ordinary skill possession of a 50-800 mg/week fixed-dose range specifically for the standard dosing phase, or by amending the claims to subject matter supported by the original disclosure.
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 15-25, 27, and 29 are rejected under 35 U.S.C. § 103 as being unpatentable over Zhang et al. (US20180228740A1, published 16 August 2018; hereinafter “Zhang”), in view of Licari et al. (US20070203110A1, published 30 August 2007; hereinafter “Licari”), and Tabibi et al. (US6682758B1, published 27 January 27 2004; hereinafter “Tabibi”).
Zhang teaches pharmaceutical compositions containing Gamitrinib and identifies Gamitrinib as a geldanamycin-derived mitochondrial Hsp90 inhibitor whose benzoquinone ansamycin backbone is derived from 17-AAG (¶[0039]-[0041]). Zhang further teaches that parenteral Gamitrinib compositions may employ liquid pharmaceutical carriers including DMSO and that injectable compositions may be sterile solutions, dispersions, or suspensions containing water, surfactants, lecithin, and sugars/isotonic agents (¶[0069]-[0083]). Zhang does not expressly disclose in one embodiment the complete seven-component formulation of instant claim 25.
Licari supplies the missing formulation architecture for the 17-AAG scaffold from which Zhang expressly states Gamitrinib is derived. Licari Example 7 discloses an aqueous nanosuspension containing 17-AAG, water for injection, polysorbate 80, soybean phosphatidylcholine (i.e., lecithin) and sucrose. Licari then teaches dilution of the formulation into 5% dextrose in water immediately before administration. Example 14 specifically demonstrates tenfold dilution into D5W and intravenous administration to beagle dogs.
Tabibi independently establishes that DMSO was a known and preferred solvent for parenterally formulating the poorly water-soluble 17-AAG scaffold. Tabibi Example 1 dissolves 17-AAG in DMSO and combines the DMSO drug solution with an aqueous phospholipid dispersion to produce a stable colloidal suspension. Tabibi identifies DMSO as a preferred water-miscible organic solvent (Example 1; claims 1, 2, 5).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, seeking a parenteral formulation for Gamitrinib, to apply Licari’s and Tabibi’s formulation teachings to Zhang’s Gamitrinib.
First, Zhang itself identifies Gamitrinib as having the 17-AAG-derived ansamycin backbone, thereby expressly linking Gamitrinib to the active pharmaceutical scaffold formulated in Licari and Tabibi. Second, Licari explains that parenteral formulation of ansamycins such as 17-AAG is difficult because of poor water solubility and specifically identifies prior DMSO/phospholipid formulation approaches for solving that problem. (¶[0010]). Third, Zhang independently instructs that choice and amount of pharmaceutical carrier are governed by “the solubility and chemical nature” of the composition and expressly identifies DMSO as an available liquid carrier. (¶[0083]-[0084]).
Thus, the prior art itself identifies Gamitrinib as a 17-AAG-derived molecule, identifies formulation of poorly water-soluble ansamycins as a known problem, and supplies established DMSO/surfactant/phospholipid/sugar aqueous formulation systems for solving that problem. Using the proven Licari/Tabibi formulation techniques for the structurally related 17-AAG-derived Gamitrinib would have constituted application of known formulation techniques to a closely related product ready for improvement, with the predictable purpose of obtaining a stable parenteral suspension (see See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007)).
One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Tabibi experimentally obtained stable 17-AAG/DMSO/phospholipid aqueous formulations and administered such formulations intravenously and Licari experimentally obtained stable 17-AAG/polysorbate-80/lecithin/sucrose nanosuspensions, diluted them with D5W, and administered them intravenously. In addition, Zhang characterizes Gamitrinib as an analog derived from the same 17-AAG scaffold and independently teaches DMSO, sterile suspensions, surfactants, and parenteral administration for Gamitrinib compositions.
Thus, the instant claimed components perform the same established pharmaceutical functions in the proposed combination, wherein DMSO assists solubilization, polysorbate 80 and lecithin provide surface-active/dispersion stabilization, sucrose and dextrose provide carbohydrate/isotonic formulation functionality, and water provides the aqueous parenteral carrier. No reference identifies an incompatibility between those excipients and Gamitrinib. Accordingly, instant claim 25 would have been obvious over Zhang in view of Licari and Tabibi.
Instant claim 27 additionally requires approximately 1-25 mg/mL Gamitrinib, 0.5-15% DMSO (v/v), 0.025-1% polysorbate 80 (w/v), 0.01-1% lecithin (w/v), 0.5-10% sucrose (w/v), and 1-15% dextrose (w/v). Licari Example 14 begins with a nanosuspension containing 50 mg/mL 17-AAG, 1% polysorbate 80, 0.25% lecithin, and 10% sucrose and expressly dilutes that formulation tenfold into D5W before intravenous administration. A tenfold dilution necessarily produces approximately 5 mg/mL active compound, 0.10% polysorbate 80, 0.025% lecithin, 1.0% sucrose, and approximately 4.5% dextrose contributed by the D5W diluent. Each of those values falls within the corresponding range recited in instant claim 27. Additionally, Tabibi dissolves the 17-AAG drug component in DMSO before addition to the aqueous phospholipid phase and teaches DMSO as a preferred solvent (Example 1; claim 5). Zhang likewise identifies DMSO as a suitable liquid carrier for Gamitrinib-containing compositions. (¶[0084]).
The concentration variables recited in instant claim 27 are conventional pharmaceutical formulation variables including drug loading, cosolvent concentration, surfactant concentration, phospholipid concentration, carbohydrate concentration, and diluent concentration. Licari and Tabibi specifically vary such amounts to obtain stable dispersions, and Zhang expressly instructs that carrier amount is determined by solubility, chemical nature, route, and ordinary pharmacological practice. Thus, the prior art establishes these quantities as result-effective formulation variables rather than arbitrary properties first recognized by the applicant.
Where the prior-art range overlaps or encompasses the claimed range, a prima facie case of obviousness ordinarily exists (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)). The present rejection is stronger than a mere range-overlap inference because Licari’s explicitly administered tenfold-diluted formulation places the principal non-DMSO components directly inside the claimed ranges. It would therefore have been routine for the skilled formulator, applying Zhang’s Gamitrinib teaching to Licari’s and Tabibi’s established ansamycin formulation systems, to adjust the DMSO and excipient quantities within the known workable amounts to provide adequate Gamitrinib solubilization, dispersion stability, and intravenous suitability. Thus, instant claim would have been obvious.
Instant claim 29 requires that the formulation be a solution or a suspension. Licari expressly characterizes its 17-AAG product as a pharmaceutical suspension/nanosuspension, including Example 14’s intravenously administered aqueous nanosuspension. Zhang independently teaches that liquid Gamitrinib compositions for parenteral use may be sterile solutions or sterile suspensions (¶ [0077]-[0082]). Accordingly, the additional limitation of instant claim 29 is explicitly taught by two of the references of the combination, and therefore instant claim 29 would have been obvious.
Instant claim 15 recites a cancer-treatment kit containing the pharmaceutical formulation addressed above and an instruction manual specifying a standard dosing phase during which the weekly Gamitrinib amount is about 50-800 mg. For the physical formulation, Zhang in view of Licari and Tabibi teaches or suggests Gamitrinib, water, DMSO, polysorbate 80, lecithin, sucrose, dextrose, and suitability for parenteral administration for the reasons set forth for instant claim 25. Zhang additionally expressly teaches Gamitrinib treatment kits. Zhang teaches kits/packages containing Gamitrinib formulations; a container formulated for the desired delivery route; instructions concerning dosing; instructions for administration daily, weekly, or monthly; vials, ampoules, prefilled syringes, and liquid dosage units; periodic discontinuous administration; and dosage units containing differing concentrations when varying doses over time are desired (¶[0094]-[0096]).
Zhang teaches that administration may occur on a regular weekly schedule and that equivalent dosages may be administered “about every week” (¶[0083]) and that an effective dosage of each active component, including Gamitrinib, may be approximately 1 μg to 1000 mg and separately provides weight-based dosage ranges of 0.1-50 mg/kg and narrower subranges (¶[0084]-[0085]). The claimed approximately 50-800 mg dose lies inside Zhang’s approximately 1 μg-1000 mg dose range, and Zhang teaches once-weekly administration. Selecting a 50-800 mg Gamitrinib dose from that disclosed range for administration once each week therefore yields a weekly amount of 50-800 mg. Because the compared quantities are the same parameter (i.e., amount of Gamitrinib administered per dose) and Zhang independently teaches once-weekly dosing, the numerical teaching is commensurate with the claimed parameter.
Moreover, Zhang states that dose is determined according to the particular compound, administration route, disease severity, and patient, and that preclinical data are used to formulate human dosage ranges (¶ [0084]-[0086]). Thus, selection of an appropriate dose within the expressly disclosed Gamitrinib range was presented by Zhang itself as ordinary therapeutic optimization. Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to place the Gamitrinib formulation suggested by Zhang/Licari/Tabibi into Zhang’s expressly disclosed Gamitrinib kit and to provide weekly dosing instructions within Zhang’s disclosed dose range. The result would have been the predictable combination of a known Gamitrinib treatment kit with a known parenteral ansamycin formulation platform. A person of ordinary skill would have reasonably expected success because Zhang itself teaches the Gamitrinib kit, weekly administration, the broad effective-dose interval, parenteral administration, and conventional adjustment of dose according to clinical circumstances.
Independently, the particular dosage information printed in the instruction manual is not entitled to patentable weight unless the informational content has a new and unobvious functional relationship with the physical kit (see In re Gulack, 703 F.2d 1381, 1384-85 (Fed. Cir. 1983); In re Ngai, 367 F.3d 1336, 1338=39 (Fed. Cir. 2004)). MPEP § 2111.05 specifically identifies a chemical kit accompanied by instructions for using the chemicals as an example ordinarily lacking the requisite functional relationship. The dosage words printed in the manual do not alter the chemical structure, composition, stability, packaging, or physical operation of the pharmaceutical formulation. Thus, absent evidence establishing a new functional relationship, the exact informational content “50-800 mg” and the label “standard dosing phase” do not independently distinguish the physical kit. Accordingly, instant claim 15 would have been obvious.
Instant claim 16 requires the cancer to comprise a solid tumor, lymphoma, or combinations thereof. Zhang identifies, among cancers contemplated for treatment, breast, lung, prostate, colorectal, brain, esophageal, stomach, bladder, pancreatic, cervical, head-and-neck and ovarian cancers and melanoma, as well as Hodgkin’s and non-Hodgkin’s lymphoma (¶[0043]). Thus, Zhang expressly teaches both alternatives recited in instant claim 16, thus, instant claim 16 would have been obvious for the reasons stated for instant claim 15.
Instant claim 17 requires Gamitrinib to be the only compound in the kit that treats, ameliorates, or prevents cancer. Although certain Zhang kit embodiments contain a MAPK inhibitor in addition to Gamitrinib, Zhang separately and expressly teaches Gamitrinib-alone therapy. Zhang states that its methods include administration of “Gamitrinib alone” and specifically describes administration of Gamitrinib alone to treat immunotherapy-resistant cancer. (¶[0111]-[0112]; Gamitrinib-alone embodiments).
Thus, one of ordinary skill in the art, prior to the instant effective filing date, t
would have understood Zhang’s kit architecture (i.e., container, dosage unit, instructions, and suitable packaging) to be equally applicable to Zhang’s disclosed Gamitrinib-alone therapeutic embodiment. Packaging Zhang’s expressly disclosed Gamitrinib monotherapy in Zhang’s expressly disclosed treatment-kit format would merely use the known packaging arrangement for the known single-agent therapy.
The resulting kit would contain Gamitrinib as its only anticancer active ingredient, while the water, DMSO, polysorbate 80, lecithin, sucrose, and dextrose function as formulation excipients rather than independently identified anticancer agents, thus instant claim 17 would have been obvious.
Instant claim 18 requires an acceleration dosing phase preceding the standard dosing phase in which the weekly amount of Gamitrinib is greater than the amount during the standard phase. Zhang states that administration may vary and that, in one embodiment, “the first dose of the composition is higher than the subsequent doses.” Zhang separately expressly teaches weekly administration and dosage intervals of approximately every week. (¶[0083]). Applying Zhang’s disclosed higher-first-dose regimen to its disclosed weekly regimen results in an initial weekly dose greater than subsequent weekly doses. Instant claim 18 does not impose a numerical minimum duration for the “acceleration dosing phase” beyond its occurrence before the standard phase. The motivation to do so derives directly from Zhang’s dosing disclosure. Zhang affirmatively teaches variable dosing and a higher initial dose. A person of ordinary skill would have reasonably expected the regimen to work because Zhang teaches both features for the same therapeutic compositions, thus instant claim 18 would have been obvious.
Instant claim 19 requires a recovery phase after the drug-dosing phase during which the subject is not administered Gamitrinib. Zhang teaches both continuous and periodic discontinuous administration and states that, where treatment is periodically discontinued, a treatment package may contain placebos during periods when the composition is not delivered (¶[0095]-[0096]). Thus, Zhang contemplates treatment protocols containing periods in which Gamitrinib-containing composition is not administered. To the extent “recovery phase” merely characterizes the purpose or name assigned in the instruction manual to such a drug-free interval, that semantic characterization does not change the physical kit and is subject to the printed-matter analysis discussed above. Thus, it would have been obvious to provide a post-treatment drug-free interval as one implementation of Zhang’s expressly disclosed discontinuous dosing schedules, with the predictable result that no Gamitrinib is administered during the defined interval and instant claim 19 therefore would have been obvious.
Instant claim 20 requires that the Gamitrinib amount during the dosing phase be “at or below a 3.33 mg/kg/dose, or … lower than a 6.25 mg/kg/dose.” Zhang discloses an effective Gamitrinib dosage range of approximately 0.1-50 mg/kg, with additional disclosed ranges of approximately 0.5-40 mg/kg, 0.7-30 mg/kg, and 1-20 mg/kg (¶[0084]-[0085]). Each disclosed range encompasses doses lower than 6.25 mg/kg, and the ranges expressly include doses at or below 3.33 mg/kg. For example, the disclosed 0.5-40 mg/kg range overlaps the claimed “at or below 3.33 mg/kg” interval throughout 0.5-3.33 mg/kg. Where the claimed numerical range overlaps or lies within a prior-art range, a prima facie case of obviousness ordinarily exists (see In re Peterson, 315 F.3d 1325, 1329–1331 (Fed. Cir. 2003)). Zhang further teaches that dose selection depends upon the particular patient, compound, mode of administration, and severity and that toxicity and efficacy are determined by conventional pharmaceutical procedures (¶ [0084]-[0086]). Accordingly, instant claim 20 would have been obvious.
Instant claim 21 depends from instant claim 15 and further requires that “a maximum serum concentration (Cmax) of Gamitrinib during the drug dosing phase is about 1400 ng/mL or less in the subject.” The additional limitation of instant claim 21 is therefore a pharmacokinetic exposure limitation resulting from administration of the Gamitrinib formulation according to the recited dosing protocol. For the reasons set forth in the rejection of instant claim 15, Zhang in view of Licari and Tabibi teaches or suggests the claimed Gamitrinib-containing parenteral pharmaceutical formulation, treatment kit, and dosing protocol.
Zhang recognizes Gamitrinib dosage and resulting systemic exposure as parameters to be selected and optimized in establishing a therapeutic regimen. Specifically, Zhang teaches that the effective dosage of Gamitrinib varies according to the particular compound, route of administration, disease and severity, and individual subject; expressly discloses Gamitrinib dosages of about 0.1-50 mg/kg, including narrower ranges of about 0.5-40 mg/kg, about 0.7-30 mg/kg, and about 1-20 mg/kg; and teaches that dosage is determined according to the condition, compound, route of delivery, age, weight, severity, and patient response (¶[0084]-[0085]). Zhang’s disclosure identifies Gamitrinib as an active component to which these dosage teachings apply.
More particularly, Zhang connects the administered dosage to the resulting systemic drug concentration. Zhang teaches that data obtained from cell-culture assays and animal studies may be used in formulating human dosage ranges, that dosage preferably lies within a range of circulating concentrations providing therapeutic activity with little or no toxicity, that a therapeutically effective dose may be formulated in animal models so as to achieve a circulating plasma concentration range that includes the IC50, and that plasma drug levels may be measured (¶[0085]-[0087]). Thus, Zhang does not merely disclose Gamitrinib dosage in the abstract. Zhang expressly directs the skilled artisan to select the administered dose according to the resulting circulating drug concentration and therapeutic/toxicity considerations. Administered dose and administration conditions were therefore recognized in the prior art as variables affecting the resulting systemic concentration of Gamitrinib.
Licari supplies additional quantitative pharmacokinetic evidence concerning the closely related 17-AAG pharmaceutical platform. Licari teaches that Gamitrinib possess a benzoquinone ansamycin backbone derived from 17-(allylamino)-17-demethoxygeldanamycin (“17-AAG”), together with a linker and mitochondrial-targeting moiety (¶[0039]-[0041]). Licari Example 14 evaluates the pharmacokinetics of an aqueous 17-AAG nanosuspension containing 50 mg/mL 17-AAG, 1% polysorbate 80, 0.25% lecithin, and 10% sucrose. The formulation was diluted tenfold into D5W and administered to male beagle dogs by a 60-minute intravenous infusion at 1.0 mg/kg. Licari reports for that intravenously administered nanosuspension a geometric-mean Cmax of 276.2 ng/mL (Example 14, Table V).
While the 276.2 ng/mL peak systemic concentration experimentally demonstrated by Licari is substantially below the approximately 1400 ng/mL upper limit recited in instant claim 21. Licari is not relied upon for the proposition that Gamitrinib necessarily possesses pharmacokinetics identical to 17-AAG. Rather, Licari provides evidence that, for the parent ansamycin pharmaceutical platform from which Zhang expressly teaches Gamitrinib was derived, dose, formulation, and infusion conditions were conventionally manipulated and pharmacokinetic exposure, including Cmax, was experimentally measured, and that an intravenous regimen could readily produce a peak systemic concentration well below 1400 ng/mL.
Measurement of systemic pharmaceutical exposure in plasma or serum was conventional well before the effective filing date. FDA pharmacokinetic guidance identifies Cmax as a measure of peak systemic exposure and describes systemic exposure by reference to plasma, serum, or blood concentration-time profiles (Evidentiary reference: FDA guidance for industry Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA, published December 2013). Accordingly, selecting serum rather than plasma as the biological matrix in which to quantify peak circulating Gamitrinib concentration would have constituted use of a conventional alternative analytical matrix, absent evidence that the claimed serum measurement produces a different or unexpected pharmacokinetic result.
A person of ordinary skill in oncology pharmacology and pharmaceutical development would have had reason to select and, as necessary, adjust Zhang’s disclosed Gamitrinib dose and administration conditions so that systemic Gamitrinib exposure remained within an efficacious but tolerable concentration range. The motivation is supplied expressly by Zhang. Zhang teaches that toxicity and therapeutic efficacy are determined by conventional pharmaceutical testing, that compounds having a favorable therapeutic index are preferred, and that dosage preferably produces an appropriate circulating concentration while minimizing toxicity. Zhang further directs the skilled artisan to use animal models to select doses producing desired circulating plasma concentrations and then use those data to determine useful human dosages. (¶[0084]-[0086]).
Accordingly, the relationship between administered Gamitrinib dose and resulting circulating systemic concentration was expressly recognized in the prior art. Optimizing dose and administration conditions to obtain an appropriate systemic exposure therefore represents optimization of a recognized result-effective variable, rather than selection of a previously unrecognized parameter. Here, Zhang expressly identifies administered dose as affecting the desired circulating concentration, gives workable Gamitrinib dosage ranges, and directs the artisan to experimentally determine circulating concentrations. Licari independently demonstrates conventional determination of Cmax for the closely related 17-AAG pharmaceutical platform and provides an experimentally achieved Cmax.
Thus, one of ordinary skill in the art, seeking an efficacious Gamitrinib regimen while controlling systemic exposure and toxicity, would have had reason to vary dose and/or administration conditions within Zhang’s disclosed parameters, measure the resulting systemic concentrations by conventional pharmacokinetic methods, and select a workable regimen producing an acceptable peak concentration. Selection of a regimen resulting in a Cmax no greater than about 1400 ng/mL would have been within that routine optimization. Zhang itself expressly directs adjustment of Gamitrinib dosage according to systemic concentration, efficacy, toxicity, administration route, and patient response. Licari confirms that Cmax was a routinely determined pharmacokinetic endpoint in the closely related ansamycin platform and that systemic concentrations substantially below the claimed ceiling were experimentally achievable.
A person of ordinary skill in the art would also have possessed a reasonable expectation of successfully obtaining a Gamitrinib exposure below approximately 1400 ng/mL by appropriate selection of dose and administration conditions because Zhang supplies broad Gamitrinib dosage ranges, including approximately 0.1-50 mg/kg and narrower subranges, expressly contemplates dose adjustment, and instructs that doses may be selected experimentally to obtain desired circulating drug concentrations. Licari empirically establishes that intravenous administration of the parent 17-AAG nanosuspension at 1 mg/kg over 60 minutes to obtain a Cmax. Zhang affirmatively instructs the artisan to determine the desired exposure experimentally.
Accordingly, while the mitochondrial-targeting moiety of Gamitrinib could alter pharmacokinetic properties relative to 17-AAG, such differences would have provided a reason to perform the routine dose/exposure measurements expressly contemplated by Zhang. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date, when administering the Gamitrinib formulation and treatment regimen rendered obvious by Zhang in view of Licari and Tabibi, to select and optimize the Gamitrinib dose and administration conditions according to Zhang’s expressly disclosed relationship between dosage and circulating drug concentration, and thereby obtain a regimen having a maximum systemic Gamitrinib concentration of about 1400 ng/mL or less. Therefore, instan claim 21 would have been obvious over Zhang in view of Licari and Tabibi.
Instant claim 22 requires that the kit additionally comprise an anti-inflammatory compound or a renal-protective compound and that the instruction manual instruct administration of that compound. Zhang teaches combining additional therapeutic agents with Gamitrinib and specifically identifies prednisone among the contemplated chemotherapeutic/additional agents (¶ [0090]-[0093]). Zhang further identifies “adrenocorticosteroids, prednisone, dexamethasone” among additional pharmaceutical agents usable with Gamitrinib (¶[0093]). Prednisone was unquestionably known before the instant effective filing date as an anti-inflammatory glucocorticoid.
Zhang teaches treatment kits containing the Gamitrinib compositions and dosing/administration instructions (¶[0094]-[0096]). Thus, the prior art itself supplies all three pertinent concepts- Gamitrinib therapy, co-administration of prednisone/adrenocorticosteroids, and Gamitrinib treatment kits containing administration instructions.
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to include the additional prednisone medication contemplated by Zhang in the treatment kit, together with instructions for its use, where that medication was selected for the treatment protocol. The result would have been the predictable packaging of therapeutic components that Zhang already teaches may be used together. To the extent patentability is asserted based solely upon the words instructing administration of prednisone, the communicated instructions additionally fall within the printed-matter principles of Ngai discussed for instant claim 15. Accordingly, instant claim 22 would have been obvious.
Instant claim 23 requires that Gamitrinib be formulated as a suspension suitable for parenteral administration. Licari expressly teaches injectable 17-AAG nanosuspensions and administers its nanosuspension intravenously to beagle dogs (Example 14). Zhang independently teaches that Gamitrinib-containing therapeutic compositions may be provided as pharmaceutically acceptable aqueous or nonaqueous sterile suspensions for parenteral administration (¶[0077]-[0082], ¶[0113]). Thus, the claimed dosage form is contemplated by Zhang itself and is experimentally demonstrated for the parent 17-AAG formulation platform in Licari and instant claim 23 therefore would have been obvious.
Instant claim 24 requires that the subject be human. Zhang defines the subject as including a human and states: “In one embodiment, the subject of these methods and compositions is a human” (¶[0042]). Zhang further teaches that animal-study data can be used to formulate dosage ranges for humans (¶[0085]=[0086]). Accordingly, treatment of a human with the claimed Gamitrinib kit was expressly contemplated, thus instant claim 24 would have been obvious.
Claims 25 and 28 are rejected under 35 U.S.C. § 103 as being unpatentable over Zhang et al. (US20180228740A1, published 16 August 2018; hereinafter “Zhang”), in view of Licari et al. (US20070203110A1, published 30 August 2007; hereinafter “Licari”), and Tabibi et al. (US6682758B1, published 27 January 27 2004; hereinafter “Tabibi”), as applied to claim 25 above, in further view of Austad et al. (US20090069281A1, published 12 March 2009; hereinafter “Austad”).
Zhang, in view of Licari and Tabibi, teach the limitations of instant claim 25, as described above, from which instant claim 28 depends, however do not explicitly teach the specific limitations of instant claim 28. Instant claim 28 requires approximately 5 mg/mL Gamitrinib, 2.5% DMSO, 0.125% polysorbate 80, 0.031% lecithin, 1.25% sucrose, and 4.375% dextrose.
As explained for instant claim 27 above, Licari Example 14 expressly administers a tenfold D5W dilution of a formulation containing 50 mg/mL 17-AAG, 1% polysorbate 80, 0.25% lecithin, and 10% sucrose. The tenfold diluted composition therefore contains approximately 5 mg/mL active compound, 0.10% polysorbate 80, 0.025% lecithin, 1.0% sucrose, and about 4.5% dextrose. Those values are strikingly close to claim 28’s approximately 5 mg/mL, 0.125%, 0.031%, 1.25%, and 4.375%, respectively.
Austad additionally demonstrates that, long before the instant effective filing date, 2.5% DMSO was a specifically selected concentration for formulating closely related geldanamycin/ansamycin derivatives together with a polysorbate surfactant. In particular, Austad describes 17-AG formulations containing 2.5% DMSO and Tween-80 and separately teaches nanosuspension production by high-shear microfluidization (¶[0262]-[0268]).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to optimize Licari’s closely approaching surfactant/phospholipid/sugar/D5W concentrations and to employ the expressly known 2.5% DMSO ansamycin cosolvent concentration when adapting that formulation platform to Zhang’s 17-AAG-derived Gamitrinib. Each variable was already known to affect solubility, dispersion, stability, and parenteral suitability. The adjustment from approximately 0.10% polysorbate 80 to approximately 0.125%, from approximately 0.025% lecithin to approximately 0.031%, from approximately 1.0% sucrose to approximately 1.25%, and from approximately 4.5% dextrose to approximately 4.375% represents only modest quantitative adjustment of known formulation components serving their established functions.
Under In re Aller, 220 F.2d 454, 456-457 (CCPA 1955), where the general conditions of a claim are disclosed in the prior art, discovery of optimum or workable ranges by routine experimentation ordinarily does not confer patentability where the variables were known to affect the result (see also MPEP § 2144.05). The present record provides a factual basis for that doctrine because Licari, Tabibi, Zhang, and Austad themselves teach varying the solvent, surfactant, phospholipid, carbohydrate, and dilution amounts for the purpose of obtaining usable ansamycin pharmaceutical formulations. Licari provides an intravenously administered 17-AAG formulation whose post-D5W-dilution concentrations closely approach five of the six non-water quantitative limitations, Austad expressly supplies the 2.5% DMSO concentration for a related ansamycin formulation, Tabibi confirms DMSO/phospholipid aqueous formulation of 17-AAG, and Zhang expressly identifies Gamitrinib as a 17-AAG-derived molecule and DMSO as a suitable Gamitrinib carrier. Accordingly, instant claim 28 would have been obvious over Zhang in view of Licari and Tabibi, further in view of Austad.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 08 September 2026, have been fully considered.
The applicant argues that amended claim 25 can no longer be anticipated by Zhang because claim 25 now requires a pharmaceutical formulation comprising in combination Gamitrinib, water, DMSO, polysorbate 80, lecithin, sucrose, and dextrose. The applicant further relies on the incorporation of that formulation into amended claim 15. The applicant’s argument is persuasive as to the anticipation ground.
Zhang teaches Gamitrinib pharmaceutical compositions, parenteral administration, sterile injectable solutions and dispersions, DMSO as a suitable liquid pharmaceutical carrier, lecithin, surfactants, isotonic sugars, and dextrose-related formulation concepts. Zhang also expressly teaches DMSO as a suitable liquid carrier for Gamitrinib compositions. Nevertheless, Zhang does not disclose, expressly or necessarily, the specific combination now required by claim 25, including the claimed selection and simultaneous presence of polysorbate 80, lecithin, sucrose, and dextrose together with Gamitrinib, water, and DMSO. Accordingly, the prior anticipation rejection cannot be sustained and has been withdrawn. The applicant’s observation that former claim 26 had not itself been rejected under § 102 does not independently establish patentability, the controlling reason for withdrawal is that the amended combination is not disclosed in the requisite arrangement by the single anticipatory reference.
The applicant argues that the Office has failed a purported “three-prong KSR test” requiring (1) motivation to combine, (2) reasonable expectation of success, and (3) express teaching of every limitation. The argument is not persuasive as a statement of the governing legal standard. The applicable Graham decision is Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966), not 1960. The obviousness inquiry considers the scope and content of the prior art, differences between the prior art and the claims, level of ordinary skill, and objective evidence where present.
In addition, KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-422 (2007), did not establish a rigid three-prong test. To the contrary, it rejected rigid application of the teaching-suggestion-motivation framework while retaining the requirement that the Office articulate a reason, supported by a rational underpinning, explaining why a skilled artisan would have made the proposed combination. MPEP § 2143 likewise instructs that obviousness cannot rest on a conclusory assertion that all elements were individually known; an objective reason for the combination must be supplied.
The applicant correctly observes, consistent with In re Mills, 916 F.2d 680, 682 (Fed. Cir. 1990), that the mere technical ability to combine references does not alone establish obviousness. But neither Mills nor KSR requires an express statement in a single reference instructing a skilled artisan to make the precise claimed combination. The motivation may arise from the references themselves, the nature of the problem to be solved, known functions of the elements, or other knowledge possessed by the ordinarily skilled artisan, provided the factual findings and reasoning are articulated without hindsight. Thus, the applicant’s assertion that the references contain “lists” of alternatives is relevant to the factual inquiry but is not dispositive.
The question is whether the cited art supplies a reason to make the particular selections and whether a skilled artisan reasonably would have expected the resulting formulation to perform its intended pharmaceutical function. MPEP § 2144.08 specifically instructs the Office to consider the number of selections and the teachings that would have directed a skilled artisan toward the claimed species, and to make express factual findings supporting the selection.
The applicant argues that Zhang, Singh, and Betageri supply only separate lists of potential excipients and provide no reason to arrive at the particular formulation of claim 25. Upon reconsideration, this argument does not overcome the § 103 rejection of amended claim 25, although the prior rationale is clarified and corrected as follows.
Zhang supplies the drug-specific starting point. Zhang is directed to Gamitrinib cancer therapy and expressly teaches pharmaceutical Gamitrinib compositions, parenteral administration, injectable solutions or dispersions, and DMSO as a suitable liquid pharmaceutical carrier. Zhang further teaches formulation principles involving lecithin, surfactants, and isotonic agents such as sugars. Thus, DMSO is not being selected solely from an unrelated processing disclosure. Zhang itself places DMSO within the pharmaceutical-carrier teachings for Gamitrinib.
Singh teaches physically stable aqueous pharmaceutical suspensions of water-insoluble drugs, in which lecithin functions as a physical-stability-enhancing additive. Singh expressly teaches adding a surfactant and expressly identifies polysorbate 20-80 surfactants, including compositions containing lecithin and polysorbate surfactant together. Singh explains that its order and combination of ingredients improve physical stability of aqueous suspensions of poorly water-soluble drugs (Abstract; ¶[0010]-[0012]; claims 1, 6-12). Betageri addresses formulation of poorly water-soluble drug substances with a phospholipid, surfactant, and solubilizing aid. Betageri expressly identifies sucrose and glucose as solubilizing aids and permits combinations thereof; it also identifies polysorbate 80 among suitable surfactants (claim 6 and corresponding process disclosure).
A person of ordinary skill seeking to formulate Zhang’s poorly water-soluble Gamitrinib for parenteral administration therefore would have had reason to employ the aqueous suspension-stabilization teachings of Singh, lecithin together with a polysorbate surfactant, and the specifically identified carbohydrate solubilizing/stabilizing aids of Betageri, including sucrose and glucose/dextrose. These teachings address the same formulation problems implicated by Zhang- solubilization or dispersion of a poorly water-soluble drug, physical stability of a liquid dispersion, and preparation of a pharmaceutically administrable composition.
The proposed combination does not depend merely upon knowledge, derived from the applicant’s disclosure, that the claimed ingredients can coexist. Singh affirmatively teaches the functional benefit of combining lecithin and polysorbate-type surfactants in aqueous suspensions, Betageri affirmatively identifies sucrose/glucose combinations for poorly water-soluble drug formulations, and Zhang itself teaches Gamitrinib pharmaceutical compositions and DMSO as a suitable liquid carrier. Thus, the selections are tied to identified formulation functions rather than arbitrary selections made solely because the applicant subsequently claimed them.
A person of ordinary skill would also have possessed a reasonable expectation of success because the proposed modification uses conventional pharmaceutical excipients for the same types of functions for which the cited references teach them. 35 U.S.C. § 103 does not require absolute predictability (see In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988)). Betageri’s disclosed process uses water-miscible solvent in forming a solution and subsequently produces a free-flowing powder. The retained DMSO limitation of amended claim 25 is addressed principally by Zhang’s express teaching of DMSO as a pharmaceutical liquid carrier.
The prior rejection of claims 15, 18, and 19 under § 103 over Zhang alone is no longer sufficient because amended claim 15 now contains the seven-component physical formulation limitation discussed above. That Zhang-alone rejection is therefore withdrawn as stated. For the physical formulation, the reasoning stated above for claim 25 applies equally to claim 15.
As to the instruction-manual content, the communicated dosing information is not accorded independent patentable weight for the reasons discussed above. Even if that informational content were accorded patentable weight, Zhang expressly teaches variable dosing schedules, including an embodiment in which the first dose is higher than subsequent doses, supporting the “acceleration dosing phase” of claim 18. Zhang additionally teaches kits containing placebos during periods when the therapeutic composition is not delivered, directly supporting a drug-free interval of the type recited as the recovery phase in claim 19. Thus, the applicant’s argument that claims 18 and 19 necessarily become patentable merely because they depend from amended claim 15 is not persuasive. The added formulation limitations must be considered, but they are addressed by the combined formulation teachings discussed above.
The applicant’s response also requires a distinction between the identity of the claimed excipients and the specific concentration limitations newly presented in claims 27 and 28. The prior rejection characterized various Singh and Betageri numerical ranges as directly overlapping the amended concentration limitations. That reasoning should not be maintained in its prior form. In particular, Singh states that its ingredient concentrations are generally expressed on a weight/weight basis, whereas amended claims 27 and 28 expressly employ mg/mL, v/v, and w/v units. Betageri’s disclosed DMSO concentration concerns a solvent used during preparation of a solution that is subsequently processed into a free-flowing powder; that process-solvent range is not a disclosure of the amount of DMSO retained in a final aqueous parenteral formulation. Ratios and percentages based on total solid content in Betageri cannot, without further factual support, simply be converted into the claimed final w/v concentrations.
Accordingly, the prior § 103 rejection of amended claims 27 and 28 over Zhang in view of Singh and Betageri is withdrawn insofar as it rests on the prior numerical-range rationale. The record presently establishes a substantial basis for the identity and functional selection of the components of claim 25, but the cited references do not, without additional evidence or factual findings, adequately establish the particular final-product concentrations recited by claims 27 and 28.
Claim 29 now recites that the formulation of claim 25 is “a solution or a suspension.” The amendment cures the prior § 112(b) problem but does not establish nonobviousness. Zhang teaches parenteral Gamitrinib compositions in liquid pharmaceutical carriers and contemplates sterile injectable solutions and dispersions, while Singh is expressly directed to aqueous pharmaceutical suspensions of poorly water-soluble drugs. Thus, the “solution or suspension” limitation of claim 29 would have been an expected physical form of the resulting parenteral pharmaceutical composition. The § 103 rejection of claim 29 is re-entered on the revised combination stated in this action.
The applicant states that claims 16, 17, and 20-24 “ultimately depend from claim 25.” This statement is factually incorrect. Claims 16-24 depend directly or indirectly from claim 15, whereas claim 29 depends from claim 25. Nevertheless, because amended claim 15 independently incorporates the physical formulation limitations now recited in claim 25, those limitations have been considered as discussed above.
The claims are rejected under § 103 on the revised ground set forth in this action. The new combination as applied to claim 15 is necessitated by the applicant’s amendment adding the formulation limitations to claim 15. The applicant’s arguments have been considered but are persuasive only to the extent expressly indicated above. Reconsideration has therefore resulted in withdrawal and modification of certain grounds or rejection and newly entered rejections as necessitated by the amendments.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (87 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
