APPLICATION OF PHARMACEUTICAL COMPOSITION HAVING SPECIFIC DRUG-TO-LIPID RATIO IN ANTITUMOR

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 . DETAILED ACTION Response to Amendment Status of the Claims Receipt of Applicant’s response, filed 10 Aug 2026 has been entered. Claims 19-45 remain pending in the application. Claims 22 and 32 are amended. Claims 1-18 are cancelled. Claims 44 and 45 are new Claims 25-31 and 39-43 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Claims 19-24, 32-38, 44, and 45 are under consideration to the extent of the elected species, i.e., that the anti-tumor drug is doxorubicin and the phosphatidylcholine is HSPC or SPC or distearoyl phosphatidylcholine (DSPC). Information Disclosure Statement The information disclosure statements (IDS) submitted on 17 Apr 2026 are in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement is being considered by the examiner. The foreign patent document CN101264056 was not considered as a copy was not provided. Objections Withdrawn Objections to the Drawings The drawing objections set forth in the Non-Final Office Action mailed 09 Mar 2026 are hereby withdrawn in light of applicant’s corrected drawings. Rejections Withdrawn Rejections Pursuant to 35 USC § 112 The rejections of claims pursuant to 35 U.S.C. 112(b) and 112(d) set forth in the Non-Final Office Action mailed 09 Mar 2026 are hereby withdrawn in light of applicants amendment of the claims. Rejections Pursuant to 35 USC § 102 The rejection of claims 19-23, 32, 33, 35, and 36 pursuant to 35 U.S.C. 102(a)(1) set forth in the Non-Final Office Action mailed 09 Mar 2026 is hereby withdrawn in light of applicant’s argument regarding molar ratio and the weight ratio and the lack of evidence provided that the prior art ratio meets the claimed ratio limitation. Rejections Pursuant to 35 USC § 103 The rejection of claims 19-24, 32, 33, 35, and 36 under 35 U.S.C. 103 as being unpatentable over Johnston et al. (Journal of Liposome Research, 18:145–157, 2008is withdrawn in light of applicant’s argument regarding molar ratio and the weight ratio and the lack of evidence provided that the prior art ratio meets the claimed ratio limitation. Rejections Maintained 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 19-24, 32, 33, and 35-38 are rejected under 35 U.S.C. 103 as being unpatentable over Drummond et al. (US 2017/0035749, published 09 Feb 2017, listed on IDS filed 30 May 2025). Drummond teaches liposome compositions useful for delivery of a variety of entities, especially therapeutic entities ([0006]) and as pharmaceutical compositions ([0128]). Drummond teaches that the entity contained in the liposome may be doxorubicin ([0097]), rendering obvious the form of a composition comprising an anti-tumor drug of doxorubicin and a liposome comprising a lipid as a carrier for the drug, as in claims 19-21. Drummond teaches that the entity-to-lipid ratio is at least from about 0.02 to about 5 ([0115]), rendering obvious the drug-lipid ratio of instant claims 19-24. 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). Drummond teaches liposomes having the size of 50-150 nm ([0145]) and provides examples of liposomes of 120 nm in size ([0154]), rendering obvious the particle size limitation of claim 32 and 33. Drummond teaches that lipid components of liposome membranes usually include cholesterol and diacylphosphatidylcholines ([0105]). Drummond teaches that incorporating highly saturated phosphoplipids such as distearoylphosphatidylcholine or hydrogenated soy phophatidylcholine in liposomal formulations of amphipathic drugs improves stability considerably compared to liposomes containing unsaturated phospholipids ([0140]), rendering obvious the phosphatidylcholine and cholesterol of claims 35-36. Drummond teaches the inclusion of N-(methoxy-poly(ethylene glycol)-oxycarbonyl)-distearoyphosphatidylethanolamine with molecular weight of 2,000 as part of a liposomal formulation ([0150], [0177], [0245]), rendering obvious the DSPE-mPEG2000 of claim 37. Drummond teaches targeting moiety ligands for the liposomes that bind into a cell and teaches the ligands may be antibody fragments and that the ligand interacts with a receptor such as HER2 ([0102]) and teaches an example using an anti-HER2 antibody fragment ([0220]), rendering obvious instant claim 38. Drummond does not expressly teach selecting the doxorubicin and liposome lipids in the claimed drug-lipid ratio with sufficient specificity to rise to the level of anticipation. However, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have formed a pharmaceutical composition comprising doxorubicin with a liposome having lipid such as hydrogenated soy phosphatidylcholine and cholesterol and having a drug-to-lipid ratio of about 0.02 to about 5. One of ordinary skill in the art would have been motivated to do so as liposome compositions useful for delivery of a variety of therapeutic entities, are taught by Drummond and doxorubicin, hydrogenated soybean phosphatidylcholine, cholesterol and drug-lipid ratios of about 0.02 to about 5 are known as suitable for such liposomal compositions. One of ordinary skill in the art would have a reasonable expectation of successfully forming a pharmaceutical composition with a liposome comprising doxorubicin, HSPC, cholesterol and a drug-to-lipid ratio of about 0.02 to about 5 as taught by Drummond since the modification of the prior art represents nothing more than the predictable use of prior art elements according to their established functions. Accordingly, the instant claims are rendered prima facie obvious over the teachings of Drummond. Response to Arguments Applicant's arguments filed 10 Aug 2026 have been fully considered but they are not persuasive. Applicant argues that Drummond’s teaching for molar ratio does not render obvious the claimed drug-to-lipid ratio as Drummond’s broadest range is a generic floor and Drummond has preferred ranges that are outside the claimed range (pages 11-12 of remarks). Applicant argues that Drummond does not provide teaching, examples, or motivation to select ratios at the low end. Applicant argues that the broadest genus of Drummond sharing a lower bound with the claims does not create a prima facie case of obviousness when other indicators are directed to ratios above the claimed ratio (page 12 of remarks). Applicant argues that the various embodiments fall outside and above the claimed range of 0.02-0.1 and that there are no working examples of a composition with a liposome encapsulated doxorubicin with a drug-to-lipid molar ratio within the claimed range (pages 12-13 of remarks). The examiner does not find these arguments persuasive. As noted by the applicant, the ratio taught by Drummond overlaps with the claimed ratio and the examiner notes that 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). Thus, there is a prima facie case of obviousness based on the overlapping ratios taught by Drummond. The arguments regarding preferred ranges of Drummond and the lack of an actual embodiment are not persuasive to overcome the prima facie case of obviousness as the rejection was made under 35 U.S.C. 103 which requires that “a patent for a claimed invention may not be obtained… if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been prima facie 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.” “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR, 550 U.S. at ___, 82 USPQ2d at 1397. “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At, 82 USPQ2d at 1396. While Drummond may have preferred ranges and may not provide a specific embodiment of the instantly claimed invention, the examiner maintains that the invention as claimed is nonetheless made obvious over Drummond. The ratio range taught by Drummond overlaps with the claimed range and merely reciting a preferred embodiment alternative to the instantly claimed ratio or not providing a specific embodiment of the ratio does teach not away from using the other ratios as additionally taught. Applicant argues that the specific combination of doxorubicin, molar drug-to-lipid ratio of 0.02-0.1, liposome particle size of 80-120 nm and PDI of 0.01-0.15 is not taught by Drummond (page 13 of remarks). Applicant points to examples of Drummond that do not fall within this composition (page 13 of remarks). Applicant argues that at least four independent selections are needed simultaneously from Drummond’s enormous disclosure and that making these selections is impermissible hindsight reconstruction (page 13 of remarks). The examiner does not find these arguments persuasive for similar reasons as those provided above. The lack of a specific embodiment and teachings that include combinations outside the scope of the claimed composition does not remove the case of obviousness from the teachings Drummond. The examiner notes that “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR, 550 U.S. at ___, 82 USPQ2d at 1397. “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At, 82 USPQ2d at 1396. Liposome compositions useful for delivery of a variety of therapeutic entities, are taught by Drummond and sizes of 50-150 nm, doxorubicin, and drug-lipid ratios of about 0.02 to about 5 are known as suitable for such liposomal compositions, rendering it obvious to for liposomal compositions with these features since the modification of the prior art represents nothing more than the predictable use of prior art elements according to their established functions. 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). Although Drummond does not provide a specific embodiment of the claimed invention with the elected species, as noted above, Drummond teaches each of these components as suitable for liposomal compositions and it would have been obvious to one of ordinary skill to incorporate them into the compositions. The rejection below was made previously and is applied again and now addresses new claims 44 and 45. Claim 34, 44, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Drummond et al. (US 2017/0035749, published 09 Feb 2017, listed on IDS filed 30 May 2025) as applied to claims 19-24, 32, 33, and 35-38 and in view of Danaei et al. (Pharmaceutics 2018, 10, 57; doi:10.3390/pharmaceutics10020057). The teachings of Drummond are described supra. Drummond does not teach the polydispersity index of the composition. This deficiency is made up for in the teachings of Danaei. Danaei teaches the impact of polydispersity index on clinical applications of lipidic nanocarrier systems (title). Danaei teaches that the tendency of lipidic nanocarriers to accumulate in the target tissue depends on their particle size distribution and that successful formulation of safe, stable and efficient nanocarriers requires the preparation of homogenous (monodisperse) populations of nanocarriers (page 8 first paragraph). Danaei teaches that in drug delivery applications using lipid-based carriers such as liposomes and nanoliposome formulations that a PDI of 0.3 and below is considered to be acceptable and indicates a homogenous population of phospholipid vesicles (page 8 last paragraph). Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have the liposomal formulation of Drummond with a PDI of 0.3 and below, which renders obvious the claimed 0.01-0.15. 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). It is known from Danaei that the homogenous or monodisperse populations of nanocarriers is important for safe, stable and efficient nanocarrier compositions and that controlling the PDI of liposomal carriers to 0.3 and below is considered acceptably monodisperse for drug delivery applications. Thus, it would have been obvious to one of ordinary skill to control the PDI of the liposome composition to 0.3 and below so as to form a homogenous (monodisperse) composition that is safe, stable and efficient for drug delivery. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references. Response to Arguments Applicant's arguments filed 10 Aug 2026 have been fully considered but they are not persuasive. Applicant argues that the claimed PDI range of 0.01-0.15 is substantially narrower than Danaei’s teaching of a PDI of 0.3 and below (page 14 of remarks). Applicant argues that Danaei does not provide motivation to select a PDI below 0.15 and argues that achieving a very low PDI value is a not a matter of routine optimization but requires specific formulation and processing conditions (page 14 of remarks). These arguments are not persuasive. The obviousness of the claimed range was not directly based on a routine optimization argument, but instead a PDI of 0.3 and below is known from denaei and encompasses the claimed range of 0.01 to 0.15 and when 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). The fact that the claimed range is narrower than the range of PDI from the prior art does not remove the obviousness of the claimed range based on the teachings of Danaei. It would have been obvious to one of ordinary skill to control the PDI of the liposome composition to 0.3 and below so as to form a homogenous (monodisperse) composition that is safe, stable and efficient for drug delivery, as is known from the teachings of Denai. Conclusion No claims are allowed. 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 extension fee 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 date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to EDWIN C MITCHELL whose telephone number is (571)272-7007. The examiner can normally be reached Mon-Fri 8:00-5:00. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /E.C.M./Examiner, Art Unit 1619 /ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600