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 .
Election/Restrictions
Applicants’ election of Group II (claims 9-12, 14-15 and 19-22) drawn to a nanoparticle comprising a core and shell, is acknowledged.
Because Applicants did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03 (a)).
As the requirement for restriction is deemed proper, it is maintained and hereby made FINAL.
Claims 1-8 and 25-27 are hereby withdrawn from further consideration by the Examiner, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. The instant claims have been examined commensurate with the scope of the elected invention. Applicants timely responded to the restriction requirement in the reply filed 2/15/26.
Accordingly, claims 9-12, 14-15 and 19-22 are under current examination.
Status of Claims
No new claim set was filed in response to the Restriction/Election requirement.
Claims 1-4, 6-12, 14-15 ,19-22 and 25-27 are pending and claims 9-12, 14-15 and 19-22 are under current examination.
Claim Objections
Claims 12 and 15 are objected to because of the following informalities:
Claim 12 recites “…wherein the targeting moiety comprises any one of: (i) a protein selected from…; (ii) a small molecule selected from…thereof.”. There is no coordinating conjunction between the two options in the list. For example, there is not an “and” or “or” after part (i).
Claim 15 recites “…wherein a molar ratio between the first modified lipid and the additional lipid is between 2:1 and 1:2; wherein a concentration of the first modified lipid within the nanoparticle is between 0.5 and 10% mol.” There is no coordinating conjunction between the two options in the list.
Appropriate correction is required.
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.
Claims 9-12, 14-15 and 19-22 are 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.
Claim 9-12, 14-15 and 19-22 are unclear in reciting “wherein: each of the first modified lipid and the additional lipid independently comprises a polymer covalently bound to a lipid” in lines 5-7 of claim 9. It is not clear which lipid in the composition of claim 9 is the “a lipid” recited in line 7. Is it a further lipid outside the scope of “the first modified lipid”, “the additional lipid” or “the phospholipid”? Or should it have antecedent basis to one of those. If it is a further lipid, the Examiner suggests amending to “a second additional lipid” or similar language in order to obviate the rejection.
Claims 10 and 11 are unclear in reciting “wherein the polymer comprises a biocompatible polymer…” in claim 10 and “wherein the polymer is a polyether…” in claim 11. It is unclear which polymer this has antecedent basis for; claims 10 and 11 are dependent on claim 9 and claim 9 requires the first modified lipid and the additional lipid to both comprise a polymer. It is unclear if “the polymer” recited in claims 10 and 11 narrowing both of these polymers or just one.
Claim Rejections - 35 USC § 102
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 9-11, 14 and 19-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hayes et al. (US 2014/01220111; published: 8/7/14), as evidenced by Salem et al. (Drug Des Devel Ther, 2015 Jul 20, 9, 3705-3727) and Cutler et al. (Mechanisms of Ageing and Development, 2001, 122, 895-908).
Hayes is directed to remote loading of sparingly-water soluble drugs into liposomes (Title).
With regards to instant claims 9-10 and 19-21, Hayes teaches a pharmaceutical formulation comprising carfilzomib (i.e., claimed bioactive molecule) encapsulated within a liposome, said liposome comprising a lipid membrane defining an internal aqueous compartment comprising said encapsulated carfilzomib, said lipid membrane comprising: (a) sphingomyelin (SM; i.e., claimed phospholipid; 45-65 mol%/total lipid); (b) cholesterol (i.e., claimed sterol; 25-50 mol%/total lipid); and (c) PEG-(1,2-distearoyl-sn-glycero-3-phosphoethanolamine) (PEG-DSPE; i.e., claimed first modified lipid covalently bound to a polymer; 0-10 mol%/total lipid), wherein said formulation is selected from a lyophilized formulation and a formulation in which said liposome is suspended in a pharmaceutically acceptable diluent (i.e., pharmaceutically acceptable carrier), wherein said liposomes are from about 40 nm to about 150 nm in diameter (overlaps with claimed range) [claims 1 and 3-6]. Hayes teaches that polyethylene glycol (PEG)-lipid conjugates have been used extensively to improve circulation times for liposome-encapsulated functional compounds, to avoid or reduce premature leakage of the functional compound from the liposomal composition and to avoid detection of liposomes by the body's immune system [0046].
With regards to both the first modified lipid and additional lipid limitations of instant claim 9, Hayes teaches the liposomes are PEGylated with DSPE-PEG-GSH conjugates (i.e., the claimed first modified lipid covalently bound to a polymer and targeting moiety having a binding affinity to a CNS receptor; up to 5 mol %) and/or DSPE-mPEG conjugates (i.e., the claimed additional lipid covalently bound to a polymer, wherein the molecular weight of PEG is typically within the range of 750-5000 daltons (overlaps both ranges recited in instant claim 10) [0047]. That is, Hayes teaches embodiments with three options: liposomes comprising (a) only DSPE-PEG-GSH conjugates, (b) only DSPE-mPEG conjugates, and (c) both DSPE-mPEG conjugates and DSPE-PEG-GSH conjugates. Although the examples in Hayes do not comprise both conjugates in the same liposome composition, the Examiner directs attention to MPEP 2131.02 (II), which states: “A genus does not always anticipate a claim to a species within the genus. However, when the species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parteA, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990)”. This is especially the case where there are only three species in the above teachings of Hayes.
With regards to the targeting moiety having a binding affinity to a CNS receptor limitation of instant claim 9, Hayes teaches that GSH is a targeting moiety [0048] and GSH has binding affinity to a CNS receptor as evidenced by Salem [see entire ref; e.g., Introduction section].
With regards to instant claim 11, Hayes teaches PEG sphingomyelin and as evidenced by Cutler, sphingomyelin has a Tm of 37 °C [See p. 896].
With regards to instant claim 14, Hayes teaches liposomes comprising (a) sphingomyelin (SM; i.e., claimed phospholipid; 45-65 mol%/total lipid); (b) cholesterol (i.e., claimed sterol; 25-50 mol%/total lipid); among other ingredients. Since the claimed ranges of phospholipid and sterol mol% overlap, such teaches a 1:1 molar ratio.
With regards to instant claim 22, Hayes teaches wherein the liposomes are incorporated into a liquid formulation for administration to a subject [0099].
Therefore, by teaching all the limitations of claims 9-11, 14 and 19-22, Hayes anticipates the instant invention as claimed.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 9-12, 14-15 and 19-22 are rejected under 35 U.S.C. 103 as being unpatentable over Hayes et al. (US 2014/0220111; published: 8/7/14), as evidenced by Salem et al. (Drug Des Devel Ther, 2015 Jul 20, 9, 3705-3727) and Cutler et al. (Mechanisms of Ageing and Development, 2001, 122, 895-908).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
As noted in the anticipation rejection above Hayes anticipates claims 9-11, 14 and 19-22 and so in anticipating these claims, said claims are also considered obvious under 35 USC 103 over Hayes for the reasons set forth below ("lack of novelty is the epitome of obviousness" May, 574 F.2d at 1089, 197 USPQ at 607 (citing In re Pearson, 494 F.2d 1399, 1402, 181 USPQ 641, 644 (CCPA 1974))).
Hayes is directed to remote loading of sparingly-water soluble drugs into liposomes (Title).
With regards to instant claims 9-10 and 19-21, Hayes teaches a pharmaceutical formulation comprising carfilzomib (i.e., claimed bioactive molecule) encapsulated within a liposome, said liposome comprising a lipid membrane defining an internal aqueous compartment comprising said encapsulated carfilzomib, said lipid membrane comprising: (a) sphingomyelin (SM; i.e., claimed phospholipid; 45-65 mol%/total lipid); (b) cholesterol (i.e., claimed sterol; 25-50 mol%/total lipid); and (c) PEG-(1,2-distearoyl-sn-glycero-3-phosphoethanolamine) (PEG-DSPE; i.e., claimed first modified lipid covalently bound to a polymer; 0-10 mol%/total lipid), wherein said formulation is selected from a lyophilized formulation and a formulation in which said liposome is suspended in a pharmaceutically acceptable diluent (i.e., pharmaceutically acceptable carrier), wherein said liposomes are from about 40 nm to about 150 nm in diameter (overlaps with claimed range) [claims 1 and 3-6]. Hayes teaches that polyethylene glycol (PEG)-lipid conjugates have been used extensively to improve circulation times for liposome-encapsulated functional compounds, to avoid or reduce premature leakage of the functional compound from the liposomal composition and to avoid detection of liposomes by the body's immune system [0046].
With regards to both the first modified lipid and additional lipid limitations of instant claim 9, Hayes teaches the liposomes are PEGylated with DSPE-PEG-GSH conjugates (i.e., the claimed first modified lipid covalently bound to a polymer and targeting moiety having a binding affinity to a CNS receptor; up to 5 mol %) and/or DSPE-mPEG conjugates (i.e., the claimed additional lipid covalently bound to a polymer, wherein the molecular weight of PEG is typically within the range of 750-5000 daltons (overlaps both ranges recited in instant claim 10) [0047]. That is, Hayes teaches embodiments with three options: liposomes comprising (a) only DSPE-PEG-GSH conjugates, (b) only DSPE-mPEG conjugates, and (c) both DSPE-mPEG conjugates and DSPE-PEG-GSH conjugates. Although the examples in Hayes do not comprise both conjugates in the same liposome composition, the Examiner directs attention to MPEP 2131.02 (II), which states: “A genus does not always anticipate a claim to a species within the genus. However, when the species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parteA, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990)”. This is especially the case where there are only three species in the above teachings of Hayes.
With regards to the targeting moiety having a binding affinity to a CNS receptor limitation of instant claim 9, Hayes teaches that GSH is a targeting moiety [0048] and GSH has binding affinity to a CNS receptor as evidenced by Salem [see entire ref; e.g., Introduction section].
With regards to instant claim 11, Hayes teaches PEG sphingomyelin and as evidenced by Cutler, sphingomyelin has a Tm of 37 °C [See p. 896].
With regards to instant claim 14, Hayes teaches liposomes comprising (a) sphingomyelin (SM; i.e., claimed phospholipid; 45-65 mol%/total lipid); (b) cholesterol (i.e., claimed sterol; 25-50 mol%/total lipid); among other ingredients. Since the claimed ranges of phospholipid and sterol mol% overlap, such teaches a 1:1 molar ratio.
With regards to instant claim 22, Hayes teaches wherein the liposomes are incorporated into a liquid formulation for administration to a subject [0099].
Ascertainment of the Difference Between the Scope of the Prior Art and Claims
(MPEP §2141.012)
Hayes does not teach an embodiment wherein the targeting moiety is one listed in instant claim 12. However, Hayes teaches a variety of targeting moieties (underlined species are claimed species) such as hyaluronic acid, anti-ErbB family antibodies and antibody fragments, lipoprotein lipase (LPL), [α]2-macroglobulin ([α]2M), receptor associated protein (RAP), lactoferrin, desmoteplase, tissue- and urokinase-type plasminogen activator (tPA/uPA), plasminogen activator inhibitor (PAI-I), tPA/uPA:PAI-1 complexes, melanotransferrin (or P97), thrombospondin 1 and 2, hepatic lipase, factor Vila/tissue-factor pathway inhibitor (TFPI), factor VIIIa, factor IXa, A[β]1-40, amyloid-[β] precursor protein (APP), C1 inhibitor, complement C3, apolipoproteinE (apoE), pseudomonas exotoxin A, CRM66, HIV-I Tat protein, rhinovirus, matrix metalloproteinase 9 (MMP-9), MMP-13 (collagenase-3), spingolipid activator protein (SAP), pregnancy zone protein, antithrombin III, heparin cofactor II, [α]1-antitrypsin, heat shock protein 96 (HSP-96), platelet-derived growth factor (PDGF), apolipoproteinJ (apoJ, or clusterin), A[β] bound to apoJ and apoE, aprotinin, angiopep-2 (TFFYGGSRGKRNNFKTEEY), very-low-density lipoprotein (VLDL), transferrin, insulin, leptin, an insulin-like growth factor, epidermal growth factors, lectins, peptidomimetic and/or humanized monoclonal antibodies, dingle chain antibodies or peptides specific for said receptors (e.g., sequences HAIYPRH and THRPPMWSPVWP that bind to the human transferrin receptor, or anti-human transferrin receptor (TfR) monoclonal antibody A24), hemoglobin, non-toxic portion of a diphtheria toxin polypeptide chain, all or a portion of the diphtheria toxin B chain, all or a portion of a non-toxic mutant of diphtheria toxin CRM197, apolipoprotein B, apolipoprotein E (e.g., after binding to polysorb-80 coating), vitamin D-binding protein, vitamin A/retinol-binding protein, vitamin B12/cobalamin plasma carrier protein, glutathione and transcobalamin-B 12 [0048].
Hayes does not teach a particular embodiment wherein the MW ratio, molar ratio and mol% recited in instant claim 15 are disclosed. However, Hayes teaches DSPE-PEG-GSH and DSPE-mPEG conjugates wherein the MW of the PEG is typically within the range of 750-5000 daltons [0046]; such allows for a 2:1 MW ratio of polymer of the first modified lipid and polymer of the additional lipid. Hayes teaches that the phospholipid composition of an exemplary PEGylated liposome may comprises up to 5-10 mol% of PEG-lipid conjugates [0047]. As indicated in 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.”
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Based on these teachings, 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 substitute one targeting moiety for another, each of which is taught by the prior art to be useful for the same purpose (GSH and lactoferrin, transferrin or insulin for the purpose of forming a complex for targeted drug delivery), in order to form a third composition to be used for the very same purpose (See MPEP 2144.06).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the invention was effectively filed, as evidenced by the references, especially in the absence of evidence to the contrary.
Thus, the claimed invention was prima facie obvious before the effective filing date of the claimed invention.
Citation of Relevant Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Gaillard et a. (Pharmacokinetics, Brain Delivery, and Efficacy in Brain Tumor-Bearing Mice of Glutathione Pegylated Liposomal Doxorubicin (2B3-101), PLOS One, 2014, 9(1), 1-10; in IDS dated 12/20/24) teaches the composition of claim 9 with the exception of an additional lipid which is bound to a polymer [see Methods sections].
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GENEVIEVE S ALLEY whose telephone number is (571)270-1111. The examiner can normally be reached Monday-Friday 8:00-5:00.
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/GENEVIEVE S ALLEY/ Primary Examiner, Art Unit 1617
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