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
Claim Status
The amended claim set of 25 Feb 2026 has been entered and reviewed. Claims 1-18 are cancelled.
Claims 19-23, 25, 27, 28, 32, 36, 38, 42 and 43 have been amended.
Claims 19-43 are pending.
Election/Restrictions
Applicant’s election without traverse of Group 1, claims 19-38, directed to a composition comprising an anti-tumor drug and a liposome, in the reply filed on 02/25/2026 is acknowledged. Applicants also elected that the anti-tumor drug is doxorubicin and the phosphatidylcholine is HSPC or SPC in response to the species election requirement. The examiner has extended the phosphatidylcholine species to include distearoyl phosphatidylcholine (DSPC).
Claims 25-31 and 39-43 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.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 and 32-38 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).
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 21 Nov 2023 and 30 May 2025 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.
Drawings
The drawings are objected to because figures 1-10 are presented with non-English text.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 32 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 32, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are intended to be required per the claim or if they are merely exemplary.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 22 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 22 recites that the drug-lipid ratio is 0.1 or less which extends beyond the lower limit of 0.02 for the drug-lipid ratio as recited in base claim 19.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 19-23, 32, 33, 35, and 36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Johnston et al. (Journal of Liposome Research, 18:145–157, 2008).
Claims 19-23 require a composition comprising an anti-tumor drug of doxorubicin and a liposome carrier for the drug and where the drug-lipid ratio is 0.02-0.1 (claim 19), 0.1 or less (claim 22) or 0.022-0.085 (claim 23). Claims 32-33 require a particle size between 80 and 120 nm. Claims 35-36 require a phosphatidylcholine (such as distearoyl phosphatidyl choline, DSPC) and cholesterol.
Johnston teaches the influence of drug-to-lipid ratio on drug release properties and liposome integrity in liposomal doxorubicin formulations (title). Johnston teaches a liposome formulation comprising doxorubicin and DSPC and cholesterol and having a drug-to-lipid ratio of 0.047 (page 148 results-page 149, Figure 1). This anticipates the limitations of claims 19-23, and 35-36. Johnston teaches the liposomes with mean diameters of 110±25 nm (page 147 Liposome Preparation), anticipating claims 32-33.
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, 35, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Johnston et al. (Journal of Liposome Research, 18:145–157, 2008).
The teachings of Johnston regarding the doxorubicin liposomes are described supra in the 102(a)(1) rejection.
Johnston does not teach the drug-lipid ratio of 0.043 as in instant claim 24 at the level of anticipation, however, this ratio is obvious from the teachings of Johnston.
Johnston teaches that there is an enhancement of drug retention when the drug-lipid ratios are increased from 0.047-0.39 for liposome doxorubicin (page 149). Johnston teaches that there is a linear relationship between the drug-to-lipid ratio and the doxorubicin release half-life (see fig 2). Johnston teaches that the trapping efficiencies are reduced from nearly 100% at an initial drug-lipid ratio of 0.05 to less than 70% at a ratio of 0.8 (page 151 middle, Fig 5). Johnston teaches that varying the drug-to-lipid ratio provides an effective means for regulating drug release from liposomal doxorubicin formulations (page 153 last paragraph).
Thus, in view of the teachings of Johnstone that the drug-to-lipid ratio is related to the trapping efficiency and provides an effective means for regulating drug release from liposomal doxorubicin formulations, it is clear that the drug-lipid ratio is an art-recognized result effective variable such that determining that the ratio is 0.043 would be a matter of optimization through routine experimentation. "[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). Johnstone teaches an embodiment with a ratio 0.047 which is close to the claimed 0.043 and teaches that the ratio can be varied as a means of regulating the drug release. 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 determined the drug-lipid ratio through routine experimentation as a means of determining the optimal drug trapping efficiency and release from the liposome.
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.
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.
Claim 34 is 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.
Conclusion
No claim is allowed.
Correspondence
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.
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/E.C.M./Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600