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 .
Status of Claims
A new claim set was filed on 6/29/26 with the following:
Amended claims
9-12, 15, 19
Newly canceled claims
20
Newly added claims
Previously canceled claims
5, 13, 16-18, 23-24
Previously withdrawn claims
1-4, 6-8, 25-27
Claims under instant examination
9-12, 14-15, 19, 21-22
Withdrawn Claim Objections/Rejections
All rejections pertaining to claim 20 are moot because the claims were cancelled in view of the amendments filed on 6/29/26.
The objections to claims 12 and 15 for minor informalities are hereby withdrawn in view of the claim amendments filed on 6/29/26.
The rejections of claims 9-12, 14-15 and 19-22 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out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention are hereby withdrawn in view of the claim amendments filed on 6/29/26.
The rejections of:
claims 9-11, 14 and 19-22 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); and
Claims 9-12, 14-15 and 19-22 under 35 U.S.C. 103 as being unpatentable over Hayes et al. (US 2014/0220111; published: 8/7/14; of record), as evidenced by Salem et al. (Drug Des Devel Ther, 2015 Jul 20, 9, 3705-3727; of record), Cutler et al. (Mechanisms of Ageing and Development, 2001, 122, 895-908; of record)
are hereby withdrawn in view of the claim amendments filed on 6/29/26.
New Claim Objections
Claims 9 and 21 are objected to because of the following informalities:
Claim 9 recites …an PEG-lipid…” in line 3. The Examiner suggests amending “an” to “a”.
Claim 9 recites “…5-hydroxytryptamine receptor, serotonin receptor…” in line 14. These are the same thing and therefore, the Examiner suggests deleting one of the duplicate terms.
Claim 21 recites “…claim 9and…”. The Examiner suggests adding a space before “and”.
Appropriate correction is required.
New Claim Rejections - 35 USC § 102
Applicant' s claim amendments have necessitated the following new grounds of rejection.
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, 10 and 21-22 are newly rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hayes et al. (US 2014/01220111; published: 8/7/14; of record), as evidenced by Cutler et al. (Mechanisms of Ageing and Development, 2001, 122, 895-908; of record) and Varga et al. (Neurochem Res. 1997, 9:1165-1171).
Hayes is directed to remote loading of sparingly-water soluble drugs into liposomes (Title).
With regards to instant claims 9-10, 19 and 20-21, 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 PEG-lipid; 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 PEG-lipid, 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 parte A, 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, as evidenced by Varga, GSH is an endogenous ligand of AMPA and NMDA receptors, which reads on the Markush group of CNS receptors recited in instant claim 9 [Abstract].
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, 19 and 21-22, Hayes anticipates the instant invention as claimed.
New Claim Rejections - 35 USC § 103
Applicant's claim amendments have necessitated the following new grounds of rejection.
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, 19 and 21-22 remain rejected under 35 U.S.C. 103 as being unpatentable over Hayes et al. (US 2014/0220111; published: 8/7/14; of record), as evidenced by Cutler et al. (Mechanisms of Ageing and Development, 2001, 122, 895-908; of record) and Varga et al. (Neurochem Res. 1997, 9:1165-1171).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Hayes is directed to remote loading of sparingly-water soluble drugs into liposomes (Title).
With regards to instant claims 9-10, 19 and 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 PEG-lipid; 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 PEG-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 PEG-lipid, 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, as evidenced by Varga, GSH is an endogenous ligand of AMPA and NMDA receptors, which reads on the Markush group of CNS receptors recited in instant claim 9 [Abstract].
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.
Response to Arguments
Applicants’ arguments with regard to the previously cited prior art are moot in view of the withdrawn claim rejections. To the extent that Applicants’ arguments are pertinent to the newly applied rejections, they are addressed as follows:
Applicants argue that as evidenced by Salem, glutathione binds to glutathione receptors in the brain and such receptors are not recited in instant claim 9 [See 102 and 103 Remarks].
This is not found persuasive. In response, the Examiner does not contend that glutathione binds to glutathione receptors. However, the above rejections provide evidence via the Varga reference, glutathione is, also, an endogenous ligand of AMPA and NMDA receptors, which reads on the Markush group of CNS receptors recited in instant claim 9 [Abstract].
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 GENEVIEVE S ALLEY whose telephone number is (571)270-1111. The examiner can normally be reached Monday-Friday 8:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached at 571-272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GENEVIEVE S ALLEY/ Primary Examiner, Art Unit 1617
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