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 and Claim Status
Applicants’ amendments and arguments filed 11/3/25 are acknowledged.
The terminal disclaimer filed on 11/3/25 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on Application Number 17638988 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Any other objection or rejection from the 6/4/25 office action that is not addressed below is withdrawn based on the amendments.
Previously, the species as set forth in the reply filed on 4/8/25 were elected.
Claims to the elected species are rejected as set forth below. Claim 25 does not recite the elected cannabinoid of CBD and thus is drawn to a non-elected species.
Claim 25 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/8/25.
Claims 4, 6-7, 10-13, 15, 18, 20, 23, 28-31 and 33-37 have been cancelled.
Claims 1-3, 5, 8-9, 14, 16-17, 19, 21-22, 24, 26-27, 32 and 38-39 are being examined.
Claim Rejections - 35 USC § 103
The rejection below is maintained from the previous office action.
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 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.
Claim(s) 1-3, 5, 8-9, 14, 16-17, 19, 21-22, 24, 26-27, 32 and 38-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Allon et al. (US 9,655,848; cited with IDS of 4/13/23; ‘Allon’) in view of Zhang et al. (citation 2 of IDS of 4/13/23; ‘Zhang’) in view of Chang et al. (citation 3 of IDS of 4/13/23; ‘Chang’) in view of Astruc-Diaz (citation 4 of IDS of 4/13/23) in view of Kim et al. (‘Methionine oxidation and reduction in proteins’ Biochimica et Biophysica Acta (1840) 2014 pages 901-905).
Allon teach a drug delivery system that ensures the crossing of the drug over the blood brain barrier (column 3 lines 21-30). Allon teach the use of a blood brain barrier recognition peptide (column 3 lines 55-57). Allon teach liposomes that include a peptide conjugated thereto (abstract and claim 1). In figure 1, Allon teach a specific peptide (AHRERMS) and conjugate. Allon teach that the conjugation is to the N-terminus of the peptide (column 9 lines 11-24).
Allon teach lipids where the hydrocarbon chains are typically about 14-22 carbon atoms in length (column 6 lines 39-46). Allon specifically recites that the phospholipid is DSPC (column 7 lines 19-24, 41 and 57). Allon teach the inclusion of cholesterol and teach a weight ratio of cholesterol to phospholipid of 1:1 (column 8 lines 20-33). Allon teach a variety of drug amounts (column 10 lines 12-21 and column 13 line 59 – column 14 line 27). Allon teach liposomes with a particular diameter including between 50 nm and 250 nm (column 12 lines 36-51). Allon teach liposomes with a particular zeta potential including -50 to -100 mV (column 12 last paragraph). Allon teach for delivering drugs to the central nervous system (CNS) specifically such that the drug is able to permeate through the blood brain barrier (column 1 lines 54-61). Allon teach for treating with applications to the brain (column 2 lines 23-30) and teach a wide range of pathologies (column 5 lines 25-50). Allon specifically refers to the therapeutic being entrapped (column 8 lines 57 – column 9 line 2).
Allon does not teach a cannabinoid nor does Allon teach a modified peptide with the R1 and R2 as claimed.
Zhang teach drug nanocarriers that comprise liposomes that contain an encapsulated drug (abstract). Zhang teach that cholesterol was compounded with either DOPC or DSPC to produce O-1 and S-1 particles (figure 2 and figure 2 caption page 299). Zhang teach that the O-1 (DOPC-based) liposomes were cytotoxic and thus excluded from further investigations while S-1 (DSPC-based) did not reveal any effect on cellular viability (page 299 first paragraph). Zhang teach that various liposome nanoparticles successfully entrapped the drug (conclusion connecting paragraph pages 303-304).
Chang teach liposome based drug formulations (title and abstract). Chang shows the structure of DSPC (figure 1) and teach that ‘Liposomes composed of phospholipids like DSPC have higher stability compared with others containing unsaturated fatty acid’ (page 54 first complete paragraph).
Astruc-Diaz teach cannabinoid delivery systems (title). Astruc-Diaz teach that cannabinoid compounds are pharmacological agents to treat neurodegenerative and neuroinflammatory diseases (page 274 first paragraph). Astruc-Diaz teach certain formulations achieved brain tissue concentrations higher than plasma drug concentrations (page 131 first complete paragraph). Astruc-Diaz recognizes functionalization to allow for delivery to specific sites such as the brain (page 170 first paragraph). Astruc-Diaz teach that cannabidiol (CBD) is from Cannabis sativa (page 29 first complete paragraph). Astruc-Diaz teach that CBD based mixtures are on the market (page 31 first paragraph of section 9). Astruc-Diaz teach that CBD can directly block calcium channels that play a role in neuropathic pain (page 30 lines 5-9). Astruc-Diaz recognizes cannabinoid receptors as regulating neuroinflammation and providing neuroprotection in brain cells (page 22 lines 3-7) and the title of reference 26 of page 45 refers to cannabinoids as neuroprotective agents. Astruc-Diaz recognizes the entrapment of drugs and the use of liposomes (page 81 first paragraph). Astruc-Diaz teach the use of therapeutic doses (page 173 first paragraph of section 11).
Kim teach that Met is subject to reversible oxidation and reduction and teach that methionine sulfoxide (MetO) is reduced back to Met by enzymes that are virtually universal among aerobic organisms (page 901 paragraph connecting columns 1-2). Kim teach that Met oxidation may lead to enhanced function including resistance to proteolysis (last complete paragraph on page 903). Kim teach a relative ease of reversible oxidation and reduction (conclusion paragraph on page 904).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Allon based on the specific teachings and suggestions of Allon and based on the advantages of using DSPC as taught by Zhang (less toxicity) and Chang (higher stability). Allon teach liposomes that include a peptide conjugated thereto (abstract and claim 1). In figure 1, Allon teach a specific peptide (AHRERMS) and conjugate. Allon teach lipids where the hydrocarbon chains are typically about 14-22 carbon atoms in length (column 6 lines 39-46). Allon teach that the conjugation is to the N-terminus of the peptide (column 9 lines 11-24). Allon specifically recites that the phospholipid is DSPC (column 7 lines 19-24, 41 and 57). Zhang teach that cholesterol was compounded with either DOPC or DSPC to protein O-1 and S-1 particles (figure 2 and figure 2 caption page 299). Zhang teach that the O-1 (DOPC-based) liposomes were cytotoxic and thus excluded from further investigations while S-1 (DSPC-based) did not reveal any effect on cellular viability (page 299 first paragraph). Chang shows the structure of DSPC (figure 1) and teach that ‘Liposomes composed of phospholipids like DSPC have higher stability compared with others containing unsaturated fatty acid’ (page 54 first complete paragraph). Thus one would have been motivated to use the saturated DSPC based fatty acid instead of the DOPC based fatty acid in the construct of Allon (see figure 1). Further, since Allon teach lipids where the hydrocarbon chains are typically about 14-22 carbon atoms in length (column 6 lines 39-46) one would have been motivated to make such constructs. Further, since Allon teach a drug delivery system that ensures the crossing of the drug over the blood brain barrier (column 3 lines 21-30) and teach for delivering drugs to the central nervous system (CNS) specifically such that the drug is able to permeate through the blood brain barrier (column 1 lines 54-61) and teach for treating with applications to the brain (column 2 lines 23-30) and teach a wide range of pathologies (column 5 lines 25-50) one would have been motivated to deliver the CBD drug as taught by Astruc-Diaz. One would have had a reasonable expectation of success since Allon (columns 17-19) and Zhang (page 295) teach methods of making liposomes. Further, Allon teach a drug delivery system that ensures the crossing of the drug over the blood brain barrier (column 3 lines 21-30). Further, since Kim teach that Met is subject to reversible oxidation and reduction and teach that methionine sulfoxide (MetO) is reduced back to Met by enzymes that are virtually universal among aerobic organisms (page 901 paragraph connecting columns 1-2) and teach that Met oxidation may lead to enhanced function including resistance to proteolysis (last complete paragraph on page 903) one would have been motivated to use the methionine sulfoxide form in the peptide of Allon.
In relation to the peptide of claims 1 and 3, in figure 1 Allon teach a specific peptide (AHRERMS) and conjugate. Allon teach that the conjugation is to the N-terminus of the peptide (column 9 lines 11-24). Allon teach a specific peptide (AHRERMS) (figure 1) that contains Met. Kim teach that Met is subject to reversible oxidation and reduction and teach that methionine sulfoxide (MetO) is reduced back to Met by enzymes that are virtually universal among aerobic organisms (page 901 paragraph connecting columns 1-2). Kim teach that Met oxidation may lead to enhanced function including resistance to proteolysis (last complete paragraph on page 903).
In relation to the modified structure as in claims 1-2, 5 and 8-9, Allon shows a specific structure (figure 1). Allon teach that the conjugation is to the N-terminus of the peptide (column 9 lines 11-24). When using the alkyl chain of DSPC instead of DOPC (compare figure 2 of Zhang), the resulting structure is such that R1 and R2 are alkyl chains, R6 is carbonyl, R5 is C2 straight alkyl and R7 is carbonyl. Further, Allon teach lipids where the hydrocarbon chains are typically about 14-22 carbon atoms in length (column 6 lines 39-46) thus suggesting the length of claim 2.
In relation to claims 14, 16-17, 19, 21-22, 27 and 32, Allon teach the inclusion of cholesterol and teach a weight ratio of cholesterol to phospholipid of 1:1 (column 8 lines 20-33). Allon specifically recites that the phospholipid is DSPC (column 7 lines 19-24, 41 and 57) which is recited in claim 16. Allon teach 0.5 mol% of the conjugated peptide (column 19 lines 7-10). Zhang teach that the O-1 (DOPC-based) liposomes were cytotoxic and thus excluded from further investigations (page 299 first paragraph) so one would have been motivated to exclude as in claim 21. There is no specific mention of including DPPA as in claim 22. Allon teach liposomes with a particular diameter including between 50 nm and 250 nm (column 12 lines 36-51). Allon teach liposomes with a particular zeta potential including -50 to -100 mV (column 12 last paragraph).
In relation to claims 1, 24, 26 and 38-39, Astruc-Diaz teach cannabidiol (CBD) (page 29 first complete paragraph) which is known to be from a plant extract (page 17 last paragraph and page 29 first complete paragraph). Allon teach a variety of drug amounts (column 10 lines 12-21 and column 13 line 59 – column 14 line 27). Allon specifically refers to the therapeutic being entrapped (column 8 lines 57 – column 9 line 2). Astruc-Diaz recognizes the entrapment of drugs and the use of liposomes (page 81 first paragraph). Astruc-Diaz teach the use of therapeutic doses (page 173 first paragraph of section 11).
Response to Arguments - 103
Applicant's arguments filed 11/3/25 have been fully considered but they are not persuasive with respect to the rejection set forth above.
Although applicants argue that claim 1 has been amended to incorporate the language of claim 4, claim 4 was previously rejected (see pages 9-14 of the 6/4/25 office action).
Although applicants argue ‘the application recites on page 7, lines 5-11, addresses US Patent 9,655,848’, it is unclear what applicants are trying to argue. Page 7 lines 5-11 of the instant application relates to liposome size. A mere mention of a reference is not enough to discredit the reference.
Although applicants argue that the peptides in the instant application have increased stability relative to those of Allon, the basis for the assertion or comparison is unclear. It is unclear which embodiment of Allon is being compared. It is unclear which embodiment of the instant application is being compared. It is unclear what measure of ‘stability’ is being compared. MPEP 716.02(b) recognizes that the burden is on the applicant to establish that results are unexpected and significant. For the reasons set forth above, there are inadequate facts to establish unexpected results.
Although applicants refer to stability tests using the general structure described in example 1A and provides results in a table, it is unclear what is meant by ‘the general structure as described in Example 1A’. Example 1A recites compounds 1-8, it is unclear which is the ‘general structure’. The conditions for the data are unclear. It is unclear what solution the structures were stored in and it is unclear if the testing was in vitro or in vivo. MPEP 716.02(b) recognizes that the burden is on the applicant to establish that results are unexpected and significant. MPEP 716.02(e) refers to comparisons with the closest prior art. The table provided does not appear to provide any comparison to any prior art.
Although applicants argue that purity could be maintained by oxidizing methionine, MPEP 716.02(c) II recognizes that expected beneficial results are evidence of obviousness. Kim teach that Met forms methionine sulfoxide due to oxygen (page 901 paragraph connecting columns 1-2). Kim teach that methionine sulfoxide (MetO) is reduced back to Met by methionine sulfoxide reductases (page 901 paragraph connecting columns 1-2). Since oxygen is present in air (and enzymes are not necessarily present in the air), normal in vitro storage conditions of a purified peptide would include air (which includes oxygen) but would not include methionine sulfoxide reductases. Based on the standard conditions of storage and the known reaction chemistry of Met, there is no basis to conclude that oxidation of Met is unexpected. Further, since methionine sulfoxide reductases are required to reduce back to Met, it is not unexpected that conditions that do not include methionine sulfoxide reductase promote the presence of methionine sulfoxide. For the reasons set forth above, there are inadequate facts to establish unexpected results including unexpected results commensurate in scope with the claimed invention (which encompasses a wide range of liposomes).
Although applicants argue that Kim alone does not teach the invention, the instant rejection is a multiple reference 103 rejection and as such any single reference does not necessarily anticipate the claims. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Although applicants argue about a lack of uniformity and lack of stability, such language does not appear in the instant claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
THIS ACTION IS MADE FINAL. 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 RONALD T NIEBAUER whose telephone number is (571)270-3059. The examiner can normally be reached M - F 6:30 - 2:30 EST.
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RONALD T. NIEBAUER
Primary Examiner
Art Unit 1658
/RONALD T NIEBAUER/Examiner, Art Unit 1658