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 .
Claim Status
Applicants' amendments and arguments filed 01/30/2026 have been fully considered.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The
following rejections and/or objections are either reiterated or newly applied. They constitute the
complete set presently being applied to the instant application.
Claims 2-5, 9-31, 35-37, 39-45 are cancelled.
Claims 32-34, 38, and 46 are withdrawn.
Claims 1 and 6-8 are under current examination. The claims were read in view of the species election of a drug combination of gemcitabine and doxorubicin in the reply filed on 07/26/2024.
New Rejections Necessitated by Claim Amendments
Claim Rejections - 35 USC § 112(a)-New Matter
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.
Claims 1 and 6-8 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain 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 at the time the application was filed, had possession of the claimed invention.
Claim 1 recites “wherein the loading efficiency of Gem is greater than about 8.8 wt%”. The specification exemplifies Gem loading efficiencies via various loading methods; the maximum loading efficiency described in the specification is 10.3 ± 1.4 wt% (paragraphs [0078] and [0083]-[0084]). The specification does not provide support for a GEM loading efficiency of every wt% greater than 8.8 wt%; accordingly claim 1 introduces new matter.
Dependent claims 6-8 require all of the limitations of claim 1, and thus also fail to comply with the written description requirement.
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.
Claims 1 and 6-8 are rejected under 35 U.S.C. 112(b) 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 1 recites the limitation “the loading efficiency of Gem is greater than about 8.8 wt%” in step “f”. This is indefinite as “greater than” requires a value of higher than 8.8 wt% while “about” encompasses values less than 8.8 wt%. The scope of values encompassed by “greater than about” is therefore indefinite, and the metes and bounds of the claim are uncertain.
Claims 6-8 are rejected under 35 U.S.C. 112(b) by virtue of their dependency on indefinite claim 1 and failure to cure the deficiency noted above.
Rejections Maintained, Modified to Address Amended Claims
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (“Mixed Liposome Approach for Ratiometric and Sequential Delivery of Paclitaxel and Gemcitabine” AAPS PharmSci Tech, published online October 2, 2017, 19, 693-699, included on IDS submitted 07/16/2021), hereafter “Liu” as evidenced by Gate Scientific (“The Technique Geek’s Blog”, June 21, 2021, https://gatescientific.com/technique-geeks-blog/f/recipes-for-phosphate-buffered-saline-pbs; of record) in view of Vogus et al. (“A hyaluronic acid conjugate engineered to synergistically and sequentially deliver gemcitabine and doxorubicin to treat triple negative breast cancer” Journal of Controlled Release 2017, 267, 191-202, included on IDS submitted 07/16/2021), hereafter “Vogus”, and Hayes et al. (US 2017/0202776 A1, published July 20, 2017; of record), hereafter “Hayes”.
Regarding instant claim 1, Liu teaches methods to prepare drug-loaded liposomes encapsulating paclitaxel (PTX), gemcitabine (GEM), and co-encapsulated PTX and GEM (abstract; pg. 694, column 1, paragraph 1). Liposomes containing PTX and GEM were prepared by a remote and small volume loading method (pg. 694, column 1, “Preparation of Liposomes”).
Here, Liu teaches the method steps of: (a) dissolving the mixed lipids of DPPC, cholesterol, and DSPE-PEG2000 in a mixture of chloroform and methanol; (b) transferring the solution to a round-bottom flask, and removing the solvent via rotary evaporation to form a thin lipid film; the mixed lipids of Liu are dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), cholesterol, and N-(carbonyl-methoxypolyethylene-glycol-2000)-1, 2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE-PEG2000) (pg. 694, column 1, “Materials” and “Preparation of Liposomes”). Liu further teaches (c) hydrating the dry film with phosphate buffered saline or 250 mM ammonium sulfate solution (aqueous media). As evidenced by Gate Scientific, phosphate buffered saline is a water-based salt solution comprising deionized water and sodium chloride (pg. 1-2, “Recipes for Phosphate Buffered Saline (PBS)”). Liu further teaches (d) briefly sonicating the liposome suspension and collecting blank liposome pellets by centrifugation; and (e) mixing the liposome and drug with a PBS solution and incubating at 60 °C for 3 h to facilitate diffusion of the drug into the liposomes. Liu further teaches, regarding (d), that liposome size and shape are readily controlled by lipid membrane extrusion (pg. 698, column 1, paragraph 1); one of ordinary skill in the art would be motivated to perform a step of extruding the hydrated film through a membrane in order to achieve liposomes with equal size and shape to achieve the same pharmacokinetics and biodistribution profile, as taught by Liu (pg. 698, column 1, paragraph 1).
Regarding instant claims 6-8, Liu exemplifies remote liposome loading using 1.5 mg of drug in 3 mL of PBS (0.5 mg/mL) and small volume loading/remote and small volume loading using 1.5 mg in 20 µL of PBS (75 mg/mL). As noted above, phosphate buffered saline comprises deionized water. It would have been prima facie obvious to one of ordinary skill in the art to adjust the concentrations of drugs in the drug solution comprising deionized water within the general concentration range suggested by Liu to obtain a desired drug loading concentration and provide the desired concentration gradient driving force for drug loading, as suggested by Liu (pg. 697, column 2, paragraph 2). From MPEP 2144.05 II. A., “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Liu does not teach the elected species of a drug solution comprising both gemcitabine and doxorubicin.
Vogus teaches that multiple chemotherapeutic drugs can be incorporated into liposomes as a combination chemotherapy vehicle that can deliver synergistic ratios of drugs directly to the tumor site at the desired schedule (pg. 191, “Introduction”, paragraphs 1-2). They further teach that gemcitabine and doxorubicin are both approved by the FDA for the treatment of breast cancer, demonstrate synergy, and have been tested in combination in a liposomal formulation (pg. 191-192, “Introduction”). Similarly, Liu teaches that combination therapy using a combination of paclitaxel and gemcitabine is used for the treatment of breast cancer (pg. 693, “Introduction” paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to substitute the paclitaxel used in the method of Liu for the doxorubicin taught by Vogus. As described above, both paclitaxel and doxorubicin are known in the art as chemotherapeutic agents for the treatment of breast cancer which can be used in liposomal formulations in combination with gemcitabine. Simple substitution of one such chemotherapeutic agent for another is withing the purview of the skilled artisan, and would yield predictable results (see MPEP 2143 B), particularly as Liu teaches that remote loading is routinely used in doxorubicin loading (pg. 697, column 2, paragraph 2).
While Liu teaches that 250 mM ammonium sulfate and sodium chloride containing aqueous solutions can each be used to hydrate the lipid film, Liu does not teach that the aqueous medium used for hydration comprises sodium chloride at a concentration of about 400 to 600 mM or that the aqueous medium comprises both ammonium sulfate and sodium chloride. Liu does not teach a gemcitabine loading efficiency of greater than about 8.8 wt%.
Hayes teaches the remote or active loading of a drug into liposomes containing a transmembrane electrochemical gradient for liposome compositions containing sparingly soluble drugs that are used to treat life-threatening diseases (abstract) such as cancer (paragraphs [0102]-[0104]). Examples of the sparingly soluble drugs include doxorubicin (paragraph [0053]). Hayes further teaches that the liposomes can be formed by dissolving the lipids in chloroform, evaporating the chloroform, and hydrating the lipid with the aqueous solution which is to be encapsulated (paragraph [0042]). Hayes further teaches that the efficiency of active loading (or remote loading, see paragraph [0064]) depends on the type and magnitude of the gradient applied (paragraph [0068]); gradients can be selected from ammonium-salt gradients, sodium salt gradients, and combinations thereof. In an exemplary embodiment, the concentration of salts, such as sodium salts, in the internal liposomes is between 1 and 1000 mM (paragraph [0069]), overlapping the range of instant claim 1. Hayes teaches that the loading efficiency (g of drug/g total lipid) is at least 10% (paragraph [0079]), overlapping the claimed range.
It would have been prima facie obvious to one of ordinary skill in the art to use an aqueous medium comprising sodium chloride at a concentration of about 400 to 600 mM and to use a combination of ammonium sulfate and sodium chloride as the lipid hydration medium in the method of Liu, taught to be capable of achieving a loading efficiency of at least 10% by weight, as suggested by Hayes. One of ordinary skill in the art could routinely optimize the concentration of sodium chloride within the range of 1 and 1000 mM taught by Hayes and optimize a combination of salts (ammonium sulfate and sodium chloride, both taught by Liu to be suitable for lipid hydration) in order to achieve an optimal gradient for efficient drug loading, as taught by Hayes (paragraphs [0068]-[0069]). Such gradients are taught to affect the loading efficiency (paragraph [0069]), and at least 10% by weight loading efficiency of drugs is achieved (paragraph [0079]); higher loading is desirable to reduce the amount of liposome administered per treatment and improve cost efficiency (paragraph [0034]), providing motivation to the skilled artisan to optimize the salt gradient and corresponding loading efficiency. From MPEP 2144.05 II. A., “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”. Further, from MPEP 2144.05 I, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Response to Arguments
Applicants’ arguments filed 01/30/2026 have been fully considered, but they are not persuasive.
Regarding the claim rejections under 35 U.S.C. 103, Applicant argues that the combination of remote and small volume or hypertonic loading unexpectedly improved the Gem loading efficiency compared to using a standard process alone. Applicant argues that the teachings of the cited art did not suggest or predict the improved results achieved by the method of the invention. Applicant argues that the cited art does not teach the claimed invention without the improper use of hindsight.
These arguments are unpersuasive. The prior art of Liu teaches, “[t]he RL and SVL methods, combined together, increased GEM loading substantially, from 0.5 to 4.2%” and further suggests creating a gradient driving force to diffuse the drug into the liposomes and precipitate as an ion complex with sulfate, an effect which is enhanced by the use of small volume loading (pg. 697, column 2, paragraph 2). The prior art of Hayes similarly teaches controlling the gradient of the internal aqueous medium of liposomes to control the loading efficiency, and teaches salt combinations and concentrations consistent with the instant claims. Thus, one of ordinary skill in the art would recognize that a combination of loading approaches and optimization of the type and magnitude of loading gradient would predictably lead to an increase in loading efficiency.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Here, as set forth in the above rejections, the teachings of prior art were within the level of ordinary skill in the art before the effective filing date of the instant invention, and the rejection does not include any knowledge gleaned only from the Applicant’s disclosure.
In view of the forgoing, and as set forth in the above rejection, the Examiner maintains that the balance of evidence suggests that the instant claims are prima facie obvious over the teachings of the modified Liu.
Conclusion
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 JUDITH M KAMM whose telephone number is (703)756-4575. The examiner can normally be reached M-F 8:00 am-4:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached at (571)272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611
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