DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The amendments received 08/15/2025 have been entered. Claims 159-167 and 170-178 are pending. Applicant’s amendments to the claims have overcome each and every objection and rejection under 35 U.S.C. 112(b) and 102 previously set forth in the Office Action mailed 05/19/2025.
New grounds of rejection are set forth herein as necessitated by amendment.
Terminal Disclaimer
The terminal disclaimer filed on 08/15/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent Numbers 10786470 and 11439612 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Information Disclosure Statement
The Information Disclosure Statement filed on 08/15/2025 is in compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
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 159-167 and 170-178 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 159, 161, and 167 have been amended to recite “12.5 wt% to 15.2 wt% of eflornithine of a pharmaceutically acceptable salt thereof by free base equivalent”. Claims 160 and 166 have been amended to recite “13.9 wt% of eflornithine or a pharmaceutically acceptable salt thereof by free base equivalent”. These amounts and ranges of a “free base equivalent” of eflornithine or a pharmaceutically acceptable salt thereof were not disclosed in the specification at the time of filing and constitute as new matter. Although Applicant has apparently arrived at these numbers by calculating the “free base equivalent” of eflornithine in eflornithine HCl H2O, there is no such disclosure that would suggest that Applicant had contemplated these amounts, or a composition comprising these amounts of eflornithine of a pharmaceutically acceptable salt thereof, at the time of filing. Correction is required.
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.
Claim(s) 159-162 and 164-165 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weis et al. (EP 0871441 B1; 2003).
Weis et al. discloses a DFMO-containing (eflornithine, see par. [0082]) oral solution comprising 15 mg sodium benzoate, 18 mg saccharin sodium, 3.0 g DFMO, 0.75 mL ethanol, 0.75 mL glycerin (glycerol), 1.5 mL propylene glycol, and water to a final volume of 15 mL (par. [0123]). Weis et al. discloses that DFMO may be present in amounts of about 0.01% to 90% by weight of the composition (par. [0091]).
It would therefore be within the ability of one of ordinary skill in the art to arrive at the instantly claimed amounts and/or ranges of each component of the aforementioned oral solution through routine optimization. One would have been motivated to do so, with reasonable expectation of success, in order to maximize the therapeutic effect and stability of the DFMO composition as the amounts of the components in the Weis et al. composition are so close to the instant invention.
Claim(s) 163, 166-167, and 170-178 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weis et al. (EP 0871441 B1; 2003) as applied to claims 159-162, 164-165 above, and further in view of Vargas Medina et al. (Journal of Thermogravimetric Analysis and Calorimetry; 2014) and Hetrick et al. (US 6199698 B1; IDS filed 04/12/2023).
Weis et al. teaches the instant invention of claim 159-162 and 164-165 as above.
Weis et al. does not teach that the saccharin sodium is saccharin sodium dihydrate, nor does Weis et al. disclose a kit comprising a pouch of solid eflornithine, a pharmaceutically acceptable excipient, and instructions to prepare an oral solution of eflornithine. Weis et al. does not disclose that the sweetening agent is aspartame, dextran, dextrose, fructose, glycerol, mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol, sucrose, compressible sugar, confectioner’s sugar, or syrup, or that the excipient is hydroxypropylmethyl-cellulose or polyvinylpyrrolidone. These limitations, however, are obvious over Weis et al. in view of Vargas Medina et al.
Weis et al. further discloses a solid formulation of DFMO-containing granules for dissolution in water, comprising 33g DFMO, lactose, corn starch, and zinc stearate as a lubricant (par. [0121]). Weis et al. additionally discloses a dry beverage base comprising grapefruit flavoring, fructose, aspartame, citric acid, and DFMO for reconstitution in water (par. [0122]). Weis et al. discloses that in solid preparations the tablet and capsule diluents can be selected from, for example, lactose, starches, microcrystalline cellulose, and powdered cellulose (par. [0071]) and sets forth a particular example wherein the tablet diluent is hydroxypropyl methylcellulose (par. [0110]). Weis et al. additionally discloses that that formulation can be in a kit of parts comprising said formulation for use as a medicament (par. [0001]) and may also include pharmaceutically acceptable carrier solutions (par. [0021]).
Vargas Medina et al. discloses that sodium saccharin appears in the hydrated form in its solid state (p. 361, col. 1, par. 1). Vargas Medina et al. additionally discloses that the dihydrate form is the most thermodynamically stable at room temperature (Abstract).
Hetrick et al. discloses a pouch for pharmaceutical products (Abstract; col. 1, lines 5-10).
It would have been prima facie obvious for one of ordinary skill in the art to substitute the saccharin sodium of Weis et al. with saccharin sodium dihydrate. One would have been motivated to do so, with reasonable expectation of success, as saccharin sodium is most stable in its dihydrate form. Moreover, one of ordinary skill in the art would be apprised that in solution, as in the instant invention or that of Weis et al., the saccharin sodium would no longer maintain its hydrate form.
It would be prima facie obvious for one of ordinary skill in the art to combine the solid compositions of Weis et al., for reconstitution in water, with a kit. One would have been motivated to do so, with reasonable expectation of success, as Weis et al. discloses that the formulations can be present in a kit for the treatment of cancer. Moreover, one would have been motivated to combine the kit with a pouch for separating the pharmaceutical products, such as that of Hetrick et al., in order to better facilitate the storage of the products for administration. Regarding the content of the instructions of the kit, as in instant claims 168 and 169, per MPEP 2112.01, the content of printed matter such as instructions does not differentiate a claimed invention from the prior art: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) (Claim at issue was a kit requiring instructions and a buffer agent. The Federal Circuit held that the claim was anticipated by a prior art reference that taught a kit that included instructions and a buffer agent, even though the content of the instructions differed, explaining "[i]f we were to adopt [applicant’s] position, anyone could continue patenting a product indefinitely provided that they add a new instruction sheet to the product.").”
It would have been prima facie obvious for one of ordinary skill in the art to substitute the lactose or corn starch of the solid granules of Weis et al. with a cellulose powder such as hydroxypropyl methylcellulose. One would have been motivated to do so, with reasonable expectation of success, as Weis et al. establishes that lactose, starches, and cellulose powders are equivalent in function and thus would be expected to yield predictable results. Moreover, it would have been prima facie obvious to adjust the amounts of the excipients, such as the sweeteners, via routine optimization, in order to arrive at an optimal formulation for administration.
Response to Arguments
Applicant's arguments filed 08/15/2025 have been fully considered but they are not persuasive.
In the Remarks filed 08/15/2025, Applicant argues that one of ordinary skill in the art would not have been motivated to modify the amounts of Weis et al. because Weis et al. did not recognize that the concentration of DFMO to be result-effective, and that the range of DFMO is critical (p. 8-10 of Remarks). This is not persuasive.
First, Weis et al. contemplates the importance of optimizing the disclosed compositions. In paragraph [0049], Weis et al. states, “It should be understood that methods for the treatment of estrogen independent breast cancer will employ a variety of formulations, dosage forms and dosing regimens, i.e., each formulation will have associated with it an optimal dosage form and dosing regimen.” Moreover, regarding DFMO in particular, Weis et al. acknowledges the relationship between unit dosage forms and therapeutically effective amounts in paragraphs [0080] and [0081] such that one of ordinary skill in the art would be apprised that the amount of DFMO in the composition could be adjusted in order to administer a therapeutically effective amount of the active pharmaceutical ingredient. Moreover, regarding result-effective variables, MPEP 2144.05(II)(B) states, “However, in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421, 82 USPQ2d at 1397 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.”
Second, while Applicant argues that the range of eflornithine is critical and leads to unexpected results, these unexpected results must be commensurate in scope with the claims. MPEP 716.02(d). Moreover, to demonstrate unexpected results over a claimed range, amounts inside and outside the claimed range should be tested. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). The instant claim 1 is drawn to a pharmaceutical composition comprising from 12.5 wt % to 15.2 wt % of eflornithine or a pharmaceutically acceptable salt thereof by free base equivalent. However, only compositions comprising 18% eflornithine hydrochloride hydrate (13.9 wt %, free base equivalent) and 20% eflornithine hydrochloride hydrate (15.4 wt %, free base equivalent) were tested in Example 7. It is unclear whether the unexpected effects would occur over the entire claimed range based on two tested concentrations, one within the range and one outside of the range. Additionally, the compositions contained sodium benzoate, saccharin sodium dihydrate, glycerol, propylene glycol, and water, wherein the glycerol and propylene glycol concentrations were also varied in Formulations 1-20 (see Table 5 on page 105). Based on the results shown in Table 6 (p. 108), and as stated in paragraph [0302], the concentrations of glycerol and propylene glycol also affect precipitation and freezing of the compositions. This unexpected effect therefore cannot be attributed to the amount of eflornithine alone. As such, the claims are substantially broader in scope than the unexpected results purported by Applicant and do not establish nonobviousness.
The rejections are therefore maintained.
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 (37 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MADELINE E BRAUN whose telephone number is (703)756-4533. The examiner can normally be reached M-F 8:30am-5:00pm ET.
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/M.E.B./Examiner, Art Unit 1624 09/20/2025
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624