DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1-9, 11-16, 18-20, 24 and 26 are pending.
Preliminary Amendments
Applicant’s preliminary amendment filed on 02/29/2024 is acknowledged. The specification was amended to update [0001] for the cross-reference to related applications paragraph and add [0002.1] an incorporation of the sequence listing statement below.
Applicant’s preliminary amendment filed 09/19/2024 is acknowledged. The specification was amended to update the statement of federally sponsored research and to remove shading from table 1 at page 32. The claims were amended to cancel 10, 17, 21-23, 25, and 27-30.
It is of note that the preliminary amendment to the specification filed 02/29/2024 inserted the reference to the sequence listing below the federally sponsored research statement, however, the substitute specification filed 09/19/2024 incorporated the listing above the federally sponsored research statement. Although the location of the sequence listing paragraph has changed, i.e., below the research statement to above, the substitute specification has been entered.
Priority
Acknowledgement is made that this application is a 371 of PCT/US2022/042445 filed 09/02/2022 and claims priority based on provisional application filed as 63/240,256 on 09/02/2021.
All claims are given the priority date of 09/02/2021.
Information Disclosure Statement
Receipt of the information disclosure statement(s) on 05/28/2024 (three of them), 10/22/2024 (two of them), and 04/10/2026 are acknowledged. The signed and initialed PTO-1449 form(s) has/have been mailed with this action.
Drawings
The drawings are objected to because of the following:
Figure 3B and 3D do not have legends.
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.
Specification
Minor informalities
The disclosure is objected to because of the following informalities: Paragraph [0015] discloses color, e.g., “where red indicates”, in line 3. It would be remedial to amend this to recite “where gray indicates”.
Appropriate correction is required.
Trademark and/or tradename
The use of the following term(s), which is/are a trade name or a mark used in commerce, has been noted in this application.
Sigma-Aldrich [0082]
MerMade [0083]
Phenomenex [0084]
Clarity [0084]
Thermofisher [0084], [0085], [0090]
Savant SpeedVac [0084]
Xbridge [0085]
Orbitrap [0085]
Biorad [0087], [00102]
MycoAlert [0089]
Lipofectamine 2000 [0090]
OptiMEM [0090]
IVIS [0014], [0015], [0016], [0017], [0018], [0090], [0099], [00103]
GelRed [0091], [0095]
ProLong Gold [0092]
Nikon Eclipse [0092]
Octet RED [0093]
Dip and Run [0093]
Agilent [0096]
Bioanalyzer [0096]
AKTA [00100]
Superdex [00100]
Synergy [00100]
Quantigene [00104]
RNAlater [00104]
GentleMACs [00104]
Prism [00105]
The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Claim(s) 1-6, 8-9, 12-18, 24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Duvall et al (US 2018/0064749 A1; published March 8th, 2018; listed on IDS filed 05/28/2024 as #2 under PG Pub) in view of Wu et al (WO 2010/141069 A2; published December 9th, 2010).
Regarding claim(s) 1-6, 8-9, 13-15, Duvall et al teaches a conjugate comprising an siRNA, a lipophilic ligand (e.g., two 16 carbon fatty acids), a branching molecule, and a hydrophilic spacer (e.g., 1 block of 45 repeats of PEG) (see image below).
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Regarding claim 12, Duvall et al teaches, “As used herein, the term “small interfering RNA” or “siRNA” refers to a double-stranded RNA molecule, 20-25 base pairs in length, with phosphorylated 5′ ends and hydroxylated 3′ ends including two overhanging nucleotides.”, (para [0038]).
Regarding claim 16, Duvall et al teaches, “The albumin-binding groups include, but are not limited to, any suitable hydrophobic and/or anionic compound. Suitable albumin-binding groups may include hydrophobic molecules and/or lipids, such as palmitate; monacyl chains of varied lengths; diacyl chains of varied lengths; chains having varied levels of saturated (double) bonds; diacids; . . . For example, in one embodiment, the RNA is directly conjugated to a divalent lipidic moiety. In another embodiment, the RNA is directly conjugated to a C18 diacyl lipid. In a further embodiments, where the albumin-binding group includes a diacid, the hydrophobic chain thereof has a carboxylic acid end functionality that improves albumin binding.”, (para [0042]).
Regarding claim 26, Duvall et al teaches, “Further provided herein, in some embodiments, is a method of gene silencing, the method comprising administering a compound comprising a RNA directly conjugated to an albumin-binding group to a subject in need thereof.”, (para [0013]).
Duvall et al does not teach wherein the hydrophilic spacer (i.e., PEG) attaches the lipophilic molecule to the branching molecule.
Regarding claim(s) 1-2, 18, Wu et al teaches branched PEG chains in reaction scheme 7, which is the synthesis of 3-choloyl-l,2-bis(methoxyhexaethylenesuccinyl glycol)-3- cholate (see image below).
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More specifically, Wu et al teaches, “In accordance with the present invention, a pharmaceutical composition can include one or more genetic vectors, antisense molecules, proteins, peptides, bioactive lipids or drugs. For example, the active agent can include one or more drugs (such as one or more anticancer drugs or other anticancer agents). Typically hydrophilic active agents will be added directly to the formulation. . . Suitable active agents that can be present in the inventive formulation include one or more genetic vectors, antisense molecules, proteins, peptides, bioactive lipids or drugs, such as are described above. The inventive PEG-lipid can be used to administer active agents that are safer in presence of PEG oligomer for intravenous use.”, (para [065] to [066]).
Further, Wu et al teaches, “Suitable agents can be selected from, for example, . ., nucleotides, polynucleotides, . . . Active agents can be . . ., antisense oligonucleotides. . .”, (para [067]). “For in vivo use, the invention provides the use of a composition as herein described containing one or more active agents for preparing a medicament for the treatment of a disease. In other words, the invention provides a method of using a composition as herein described, containing one or more active agents, for treating a disease.”, (para [071).
Moreover, Wu et al teaches chemical structure 13 and that X and L are the same or different linkers, where n is the number of repeating units of PEG, and wherein terminal groups besides methyl may be included on the PEG chains (para [076]; image below).
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Wu et al teaches that “Embodiments of the present invention are described herein in the context of preparation of pharmaceutical compositions including purified PEG-lipid conjugates for increasing the solubility and enhancing the delivery of active agents. The approximate preferable compositions for formulated drug products are generally described herein, though different drugs typically have differing optimal formulations.”, (para [0077]).
Wu et al teaches, “Syntheses of polyethyleneglycol (PEG)-lipid conjugates are disclosed. Such syntheses involve stepwise addition of small PEG oligomers to a glycerol backbone until the desired chain size is attained. Polymers resulting from the syntheses are highly monodisperse. The present invention provides several advantages such as simplified synthesis, high product yield and low cost for starting materials. The present synthesis method is suitable for preparing a wide range of conjugates. In another aspect, the invention comprises PEG lipid conjugates having a glycerol backbone covalently attached to one or two monodisperse PEG chains and one or two lipids.”, (para [007] to [008]).
Regarding claim 24, Wu et al teaches, “The PEG-lipid in present invention can be used for preparing various dosage forms including tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, eye drop, powders and sprays in addition to suitable water-soluble or water-insoluble excipients.”, (para [069]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Duvall et al, i.e., an siRNA attached to a PEG45 attached to a branching molecule attached to two lipids, with the teachings of Wu et al, i.e., incorporating PEG oligomers after the branching point, to yield the predictable results a conjugate comprising an siRNA attached to a PEG45 attached to a branching molecule attached to PEG oligomers attached to the lipids individually. One would be motivated to do so because Wu et al teaches that branched PEG-Lipid conjugates: (a) are highly monodispersed, (b) simplify synthesis, (c) have a high yield, (d) have a low cost of starting material, (e) increase solubility, and (f) enhance the delivery of active agents. One could have looked to the teachings of both Duvall et al and Wu et al, and combine, i.e., inserted the PEG after the branching point, and arrived at the claimed invention with a high-likelihood of success.
Accordingly, claim(s) 1-6, 8-9, 12-18, 24, and 26 are unpatentable over Duvall et al in view of Wu et al.
Claim(s) 7, 11, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Duvall et al (supra) in view of Wu et al (supra) as applied to claim(s) 1-6, 8-9, 12-18, 24, and 26 above, and further in view of Darrell (US 2013/0295129 A1; published November 7th, 2013).
Of note: “plurality” in claim 14 is being interpreted as “more than one”.
Duvall et al in view of Wu et al do not teach (a) wherein the hydrophilic blocks are attached to each other through phosphorothioate linkages (claim 7), (b) wherein the oligonucleotide has a plurality of phosphorothioate linkages, and (c) wherein the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage.
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Regarding claim(s) 7 and 19, Darrell teaches a PEG linker attached to a lipid tail in figure 1A and C, wherein the PEG blocks are each attached via a phosphorothioate bond and wherein the lipid is attached the PEG linker via a phosphorothioate bond, see image below.
Darrell et al further teaches, “To identify an optimal albumin-binding domain that could be appended to either CpG or peptide antigens, a series of amphiphilic 20-base phosphorothioate (PS)-stabilized CpG oligos linked to various lipophilic tails via the 5' end (amph-CpGs) 3'-labeled with fluorescein amidite were constructed (FAM, FIG. 1A) and the interaction of these amphiphiles with serum proteins by size exclusion chromatography was evaluated (SEC, FIG. 2B). Fetal bovine serum (FBS) exhibited a major fraction of protein eluting at 5.3 min in SEC (coinciding with serum albumin). Diacyl lipid-conjugated CpGs (lipo-CpGs) in aq. solution eluted as micelles (3.7 min), but following incubation with 20% FBS for 2 hr, .about.46% of this amph-CpG co-migated with albumin (FIG. 2B). In contrast, the vast majority of mono-acyl-(C18-CpG) and cholesterol-(Cho-CpG) oligos eluted as unimers at 5.8 min essentially identical to unmodified CpG in the presence or absence of serum, indicating stability of the PS backbone against serum nuclease degradation and a lack of interaction with albumin (FIG. 2B).”, (para [0223]).
Regarding claim 11, Darrell et al teaches, “Modifications of the phosphate backbone may also include the substitution of a sulfur atom for one of the non-bridging oxygens in the phosphodiester linkage. This substitution creates a phosphorothioate internucleotide linkage in place of the phosphodiester linkage. Oligonucleotides containing phosphorothioate internucleotide linkages have been shown to be more stable in vivo.”, (para [0088]). Darrell also teaches claim 12, which is “The conjugate of claim 1 wherein the immunostimulatory oligonucleotide has a phosphorothioate (PS) backbone.”.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to substitute the phosphodiester bonds in the conjugate as taught by the combined Duvall et al and Wu et al, with phosphorothioate bonds as taught by Darrell et al to yield the predictable results of (a) PEG oligomers connected via phosphorothioate linkages, (b) the connection between PEG and the lipophilic molecule is a phosphorotioate linkage, and (c) the oligonucleotide backbone is composed of all phosphorothioate linkages. Both phosphodiester and phosphorothioate linkages were known in the art before the filing date of the claimed invention. One would be motivated to make such a substation because Darrell et al teaches (a) oligonucleotides containing PS linkage are more stable in vivo and (b) the PS backbone protects against serum nuclease degradation. One could have looked to the teachings of Duvall et al in view of Wu et al and Darrell et al and pursued a PS linkage substitution to arrive at the claimed invention with a high likelihood of success.
Accordingly, claim(s) 7, 11, and 19 are rejected as being unpatentable over Duvall et al in view of Wu et al, in further view of Darrell et al.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Duvall et al (supra) in view of Wu et al (supra) as applied to claim(s) 1-6, 8-9, 12-18, 24, and 26 above, and further in view of Chappell et al (Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice, Nucleic Acids Research, Vol 48, Issue 8, Pages 4382-4395, published March 17th, 2020).
Duvall et al teaches, “The albumin-binding groups include, but are not limited to, any suitable hydrophobic and/or anionic compound. Suitable albumin-binding groups may include hydrophobic molecules and/or lipids, such as palmitate; . . .”, (para [0042]).
Duvall et al in view of Wu et al does not teach wherein the conjugate has a binding affinity (Kd) to albumin of less than 1uM.
Chappell et al teaches, “Notably, the affinity for albumin, by far the most abundant plasma protein, increased 200-fold with conjugation of palmitate from 56 μM for ASO to 218 nM for Palm-ASO.”, (p. 4387, col 2, para 3).
Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to substitute the lipophilic molecules from the combination of Duvall et al in view of Wu et al, with a palmitate as suggested by Duvall et al and taught by Chappell et al to yield the predictable results of a conjugate having a binding affinity of less than 1uM. Palmitate is a known albumin binding lipid, and was known before the filing date. One of skill in the art would be motivated to utilize palmitate as the lipophilic ligand because Chappell et al teaches that Palm-ASO conjugates have a 218nM affinity to albumin. Thus, one of skill could look to the teachings of Duvall et al in view of Wu et al and the teachings of Chappell et al, and substitute the lipophilic ligand for palmitate and arrive at the claimed invention with a high likelihood of success.
Accordingly, claim 20 is unpatentable over Duvall et al in view of Wu et al in further view of Chappell et al.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim(s) 1-9, 11-16, 18-20, 24, and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1, 15-20, 26-31, 33, 35, and 39 of copending Application No. 18/177,068 (reference application). The claims of ‘068 relate to a method of treating inflammatory disease through the administration of a conjugate. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Instant claim set
‘068 claims filed 07/20/2026
1. A conjugate comprising: an oligonucleotide; a lipophilic ligand capable of binding albumin; and a linker attaching the oligonucleotide and the lipophilic ligand, the linker comprising a branching molecule attached to the oligonucleotide, and a hydrophilic spacer attaching the branching molecule and the lipophilic ligand.
8. The conjugate of claim 1, wherein the oligonucleotide comprises DNA, RNA, synthetic mimics of DNA or RNA, or a combination thereof.
or
9. The conjugate of claim 1, wherein the oligonucleotide comprises siRNA, miRNA or a single stranded antisense oligonucleotide.
or
19. The conjugate of claim 1, wherein the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage.
24. A composition comprising: the conjugate of claim 1; and one or more pharmaceutically acceptable excipients.
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26. A composition comprising: the conjugate of claim 1; and one or more pharmaceutically acceptable excipients.
1. A method of treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, optionally in combination with a pharmaceutically acceptable excipient wherein the conjugate comprises a siRNA capable of inhibiting expression of a protein associated with the inflammatory disease… ; a lipophilic ligand capable of binding albumin; and a linker attaching the siRNA to the lipophilic ligand, the linker comprising a branching molecule attached to the siRNA, and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand; wherein the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage;…
2. The conjugate of claim 1, wherein the branching molecule includes at least one branch point having at least two independent branches.
15. The method of claim 1, wherein the branching molecule includes at least one branch point having at least two independent branches.
3. The conjugate of claim 1, wherein the hydrophilic spacer comprises 1 to 100 hydrophilic blocks.
16. The method of claim 1, wherein the hydrophilic spacer comprises 1 to 100 hydrophilic blocks.
4. The conjugate of claim 3, wherein each hydrophilic block comprises 1 to 150 repeats of a hydrophilic compound.
17. The method of claim 16, wherein each hydrophilic block comprises 1 to 150 repeats of a hydrophilic compound.
5. The conjugate of claim 4, wherein the hydrophilic compound comprises ethylene glycol, zwitterionic linkers, peptoids, amino acids, poly(glycerols), poly(oxazoline), poly(acrylamide), poly(N-acryloyl morpholine, poly(N,N-dimethyl acrylamide), poly(2-hydroxypropyl methacrylamide), poly(2-hydroxyethyl methacryalmide), or a combination thereof.
18. The method of claim 17, wherein the hydrophilic compound comprises ethylene glycol, zwitterionic linkers, peptoids, amino acids, poly(glycerols), poly(oxazoline), poly(acrylamide), poly(N-acryloyl morpholine, poly(N,N-dimethyl acrylamide), poly(2- hydroxypropyl methacrylamide), poly(2-hydroxyethyl methacryalmide), or a combination thereof.
6. The conjugate of claim 4, wherein each hydrophilic block comprises 1 to 100 repeats of ethylene glycol.
19. The method of claim 17, wherein each hydrophilic block comprises 1 to 100 repeats of ethylene glycol.
7. The conjugate of claim 4, wherein the hydrophilic blocks are attached to each other through phosphorothioate linkages.
20. The method of claim 17, wherein the hydrophilic blocks are attached to each other through phosphorothioate linkages.
11. The conjugate of claim 1, wherein the oligonucleotide comprises a plurality of phosphorothioate linkages.
26. The method of claim 1, wherein the siRNA comprises a plurality of phosphorothioate linkages.
12. The conjugate of claim 1, wherein the oligonucleotide has about 15 nucleotides to about 40 nucleotides.
27. The method of claim 1, wherein the siRNA has about 15 nucleotides to about 40 nucleotides.
13. The conjugate of claim 1, wherein the lipophilic ligand comprises a lipid including a C12-C22 hydrocarbon chain.
28. The method of claim 1, wherein the lipophilic ligand comprises a lipid including a C12-C22 hydrocarbon chain.
14. The conjugate of claim 1, wherein the lipophilic ligand is divalent.
29. The method of claim 1, wherein the lipophilic ligand is divalent.
15. The conjugate of claim 1, wherein the lipophilic ligand comprises two independent lipids, each lipid including a C12-C22 hydrocarbon chain.
30. The method of claim 1, wherein the lipophilic ligand comprises two independent lipids, each lipid including a C12-C22 hydrocarbon chain.
16. The conjugate of claim 15, wherein each lipid includes a C18 hydrocarbon chain.
31. The method of claim 30, wherein each lipid includes a C18 hydrocarbon chain.
18. The conjugate of claim 2, wherein each branch is attached to an individual hydrophilic spacer, and each hydrophilic spacer is attached to an individual lipid of the lipophilic ligand.
33. The method of claim 15, wherein each branch is attached to an individual hydrophilic spacer, and each hydrophilic spacer is attached to an individual lipid of the lipophilic ligand.
20. The conjugate of claim 1, wherein the conjugate has a binding affinity (Kd)to albumin of less than 1 uM.
35. The method of claim 1, wherein the conjugate has a binding affinity (Kd) to albumin of less than 1 uM.
39. The method of claim 1, wherein the conjugate comprises a lipophilic ligand capable of binding albumin, the lipophilic ligand comprising two independent lipids, each lipid including a C18 hydrocarbon chain; anda linker attaching the siRNA to the lipophilic ligand, the linker comprising a branching molecule attached to the siRNA and including at least one branch point having at least two independent branches, anda hydrophilic spacer attaching an individual branch to an individual lipid, the hydrophilic spacer including 1 to 6 hydrophilic blocks, each hydrophilic block including 2 to 10 repeats of ethylene glycol.
Instant claim(s) 1-9, 11-16, 18-20, 24, and 26 are rejected on the ground of nonstatutory double patenting as being provisionally anticipated over claim(s) 1, 15-20, 26-31, 33, 35 and 39 of ‘068.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim(s) 1-9, 11-16, 18-20, 24, and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1, 14-19, 24-29, 31-33, and 37-38 of copending Application No. 18/737,720 (reference application). The claims of ‘720 relate to a method of treating central nervous system disease through the administration of a conjugate. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Instant claim set
‘720 claims filed 06/07/2024
1. A conjugate comprising: an oligonucleotide; a lipophilic ligand capable of binding albumin; and a linker attaching the oligonucleotide and the lipophilic ligand, the linker comprising a branching molecule attached to the oligonucleotide, and a hydrophilic spacer attaching the branching molecule and the lipophilic ligand.
8. The conjugate of claim 1, wherein the oligonucleotide comprises DNA, RNA, synthetic mimics of DNA or RNA, or a combination thereof.
or
9. The conjugate of claim 1, wherein the oligonucleotide comprises siRNA, miRNA or a single stranded antisense oligonucleotide.
24. A composition comprising: the conjugate of claim 1; and one or more pharmaceutically acceptable excipients.
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26. A composition comprising: the conjugate of claim 1; and one or more pharmaceutically acceptable excipients.
1. A method of treating a central nervous system (CNS) disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, optionally in combination with a pharmaceutically acceptable excipient, wherein the conjugate comprises a siRNA capable of inhibiting expression of a protein associated with the CNS disease; a lipophilic ligand capable of binding albumin; and a linker attaching the siRNA to the lipophilic ligand, the linker comprising a branching molecule attached to the siRNA, and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand.
38. A method of delivering a therapeutic to a central nervous system (CNS) of a subject in need thereof, the method comprising: administering a conjugate to the subject intravenously or intracerebroventricularly, wherein the conjugate localizes to the subject’s CNS, and wherein the conjugate comprises a siRNA capable of inhibiting expression of a protein associated with the CNS disease; a lipophilic ligand capable of binding albumin; and a linker attaching the siRNA to the lipophilic ligand, the linker comprising a branching molecule attached to the siRNA, and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand.
2. The conjugate of claim 1, wherein the branching molecule includes at least one branch point having at least two independent branches.
14. The method of claim 1, wherein the branching molecule includes at least one branch point having at least two independent branches.
3. The conjugate of claim 1, wherein the hydrophilic spacer comprises 1 to 100 hydrophilic blocks.
15. The method of claim 1, wherein the hydrophilic spacer comprises 1 to 100 hydrophilic blocks.
4. The conjugate of claim 3, wherein each hydrophilic block comprises 1 to 150 repeats of a hydrophilic compound.
16. The method of claim 15, wherein each hydrophilic block comprises 1 to 150 repeats of a hydrophilic compound.
5. The conjugate of claim 4, wherein the hydrophilic compound comprises ethylene glycol, zwitterionic linkers, peptoids, amino acids, poly(glycerols), poly(oxazoline), poly(acrylamide), poly(N-acryloyl morpholine, poly(N,N-dimethyl acrylamide), poly(2-hydroxypropyl methacrylamide), poly(2-hydroxyethyl methacryalmide), or a combination thereof.
17. The method of claim 16, wherein the hydrophilic compound comprises ethylene glycol, zwitterionic linkers, peptoids, amino acids, poly(glycerols), poly(oxazoline), poly(acrylamide), poly(N-acryloyl morpholine, poly(N,N-dimethyl acrylamide), poly(2- hydroxypropyl methacrylamide), poly(2-hydroxyethyl methacryalmide), or a combination thereof.
6. The conjugate of claim 4, wherein each hydrophilic block comprises 1 to 100 repeats of ethylene glycol.
18. The method of claim 16, wherein each hydrophilic block comprises 1 to 100 repeats of ethylene glycol.
7. The conjugate of claim 4, wherein the hydrophilic blocks are attached to each other through phosphorothioate linkages.
19. The method of claim 16, wherein the hydrophilic blocks are attached to each other through phosphorothioate linkages.
11. The conjugate of claim 1, wherein the oligonucleotide comprises a plurality of phosphorothioate linkages.
24. The method of claim 1, wherein the siRNA comprises a plurality of phosphorothioate linkages.
12. The conjugate of claim 1, wherein the oligonucleotide has about 15 nucleotides to about 40 nucleotides.
25. The method of claim 1, wherein the siRNA has about 15 nucleotides to about 40 nucleotides.
13. The conjugate of claim 1, wherein the lipophilic ligand comprises a lipid including a C12-C22 hydrocarbon chain.
26. The method of claim 1, wherein the lipophilic ligand comprises a lipid including a C12-C22 hydrocarbon chain.
14. The conjugate of claim 1, wherein the lipophilic ligand is divalent.
27. The method of claim 1, wherein the lipophilic ligand is divalent.
15. The conjugate of claim 1, wherein the lipophilic ligand comprises two independent lipids, each lipid including a C12-C22 hydrocarbon chain.
28. The method of claim 1, wherein the lipophilic ligand comprises two independent lipids, each lipid including a C12-C22 hydrocarbon chain.
16. The conjugate of claim 15, wherein each lipid includes a C18 hydrocarbon chain.
29. The method of claim 28, wherein each lipid includes a C18 hydrocarbon chain.
18. The conjugate of claim 2, wherein each branch is attached to an individual hydrophilic spacer, and each hydrophilic spacer is attached to an individual lipid of the lipophilic ligand.
31. The method of claim 14, wherein each branch is attached to an individual hydrophilic spacer, and each hydrophilic spacer is attached to an individual lipid of the lipophilic ligand.
19. The conjugate of claim 1, wherein the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage.
32. The method of claim 1, wherein the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage.
20. The conjugate of claim 1, wherein the conjugate has a binding affinity (Kd)to albumin of less than 1 uM.
33. The method of claim 1, wherein the conjugate has a binding affinity (Kd) to albumin of less than 1 uM.
37. The method of claim 1, wherein the conjugate comprises a lipophilic ligand capable of binding albumin, the lipophilic ligand comprising two independent lipids, each lipid including a C18 hydrocarbon chain; anda linker attaching the siRNA to the lipophilic ligand, the linker comprising a branching molecule attached to the siRNA and including at least one branch point having at least two independent branches, anda hydrophilic spacer attaching an individual branch to an individual lipid, the hydrophilic spacer including 1 to 6 hydrophilic blocks, each hydrophilic block including 2 to 10 repeats of ethylene glycol.
Instant claim(s) 1-9, 11-16, 18-20, 24, and 26 are rejected on the ground of nonstatutory double patenting as being provisionally anticipated over claim(s) 1, 14-19, 24-29, 31-33, and 37-38 of ‘720.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim(s) 1-6, 8-9, 13-16, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10 of U.S. Patent No. 11,147,827 B2 in view of Wu et al (supra).
Claim 10 of ‘827 recites, “A compound comprising siRNA functionalized with a dibenzocyclooctyne moiety and directly conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000], wherein the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] is complexed with, or remains free to complex with, albumin.”
Claim 10 of ‘827 does not require wherein the hydrophilic spacer (i.e., PEG) attaches the lipophilic molecule to the branching molecule.
Wu et al teaches branched PEG chains in reaction scheme 7, which is the synthesis of 3-choloyl-l,2-bis(methoxyhexaethylenesuccinyl glycol)-3- cholate (see image below).
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More specifically, Wu et al teaches, “In accordance with the present invention, a pharmaceutical composition can include one or more genetic vectors, antisense molecules, proteins, peptides, bioactive lipids or drugs. For example, the active agent can include one or more drugs (such as one or more anticancer drugs or other anticancer agents). Typically hydrophilic active agents will be added directly to the formulation. . . Suitable active agents that can be present in the inventive formulation include one or more genetic vectors, antisense molecules, proteins, peptides, bioactive lipids or drugs, such as are described above. The inventive PEG-lipid can be used to administer active agents that are safer in presence of PEG oligomer for intravenous use.”, (para [065] to [066]).
Further, Wu et al teaches, “Suitable agents can be selected from, for example, . ., nucleotides, polynucleotides, . . . Active agents can be . . ., antisense oligonucleotides. . .”, (para [067]). “For in vivo use, the invention provides the use of a composition as herein described containing one or more active agents for preparing a medicament for the treatment of a disease. In other words, the invention provides a method of using a composition as herein described, containing one or more active agents, for treating a disease.”, (para [071).
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Moreover, Wu et al teaches chemical structure 13 and that X and L are the same or different linkers, where n is the number of repeating units of PEG, and wherein terminal groups besides methyl may be included on the PEG chains (para [076]; image below).
Wu et al teaches that “Embodiments of the present invention are described herein in the context of preparation of pharmaceutical compositions including purified PEG-lipid conjugates for increasing the solubility and enhancing the delivery of active agents. The approximate preferable compositions for formulated drug products are generally described herein, though different drugs typically have differing optimal formulations.”, (para [0077]).
Wu et al teaches, “Syntheses of polyethyleneglycol (PEG)-lipid conjugates are disclosed. Such syntheses involve stepwise addition of small PEG oligomers to a glycerol backbone until the desired chain size is attained. Polymers resulting from the syntheses are highly monodisperse. The present invention provides several advantages such as simplified synthesis, high product yield and low cost for starting materials. The present synthesis method is suitable for preparing a wide range of conjugates. In another aspect, the invention comprises PEG lipid conjugates having a glycerol backbone covalently attached to one or two monodisperse PEG chains and one or two lipids.”, (para [007] to [008]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of claim 10 of ‘827, i.e., an siRNA attached to a PEG45 attached to a branching molecule attached to two lipids, with the teachings of Wu et al, i.e., incorporating PEG oligomers after the branching point, to yield the predictable results a conjugate comprising an siRNA attached to a PEG45 attached to a branching molecule attached to PEG oligomers attached to the lipids individually. One would be motivated to do so because Wu et al teaches that branched PEG-Lipid conjugates: (a) are highly monodispersed, (b) simplify synthesis, (c) have a high yield, (d) have a low cost of starting material, (e) increase solubility, and (f) enhance the delivery of active agents. One could have looked to the teachings of both claim 10 of 827 and Wu et al, and combine, i.e., inserted the PEG after the branching point, and arrived at the claimed invention with a high-likelihood of success.
Instant claim(s) 1-6, 8-9, 13-16, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10 of 827 in view of Wu et al.
Claim 20 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10 of U.S. Patent No. 11,147,827 B2 in view of Wu et al (supra) as applied to claim(s) 1-6, 8-9, 13-16, and 18 above, and further in view of Chappell et al (supra).
Claim 10 of 827 in view of Wu et al does not teach wherein the conjugate has a binding affinity (Kd) to albumin of less than 1uM.
Chappell et al teaches, “Notably, the affinity for albumin, by far the most abundant plasma protein, increased 200-fold with conjugation of palmitate from 56 μM for ASO to 218 nM for Palm-ASO.”, (p. 4387, col 2, para 3).
Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to substitute the lipophilic molecules from the combination of claim 10 of 827 in view of Wu et al, with a palmitate as taught by Chappell et al to yield the predictable results of a conjugate having a binding affinity of less than 1uM. Palmitate is a known albumin binding lipid, and was known before the filing date. One of skill in the art would be motivated to utilize palmitate as the lipophilic ligand because Chappell et al teaches that Palm-ASO conjugates have a 218nM affinity to albumin. Thus, one of skill could look to the claim of 827 in view of Wu et al and the teachings of Chappell et al, and substitute the lipophilic ligand for palmitate and arrive at the claimed invention with a high likelihood of success.
Accordingly, instant claim 20 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10 of 827 in view of Wu et al in further view of Chappell et al.
Claim(s) 1-6, 8-9, 13-16, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of U.S. Patent No. 12,201,644 B2 in view of Wu et al (supra).
Claim 2 of ‘644 recites, “The compound of “A compound comprising siRNA functionalized with a dibenzocyclooctyne moiety and directly conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000].”, wherein the compound is complexed with albumin.”
Claim 2 of ‘644 does not require wherein the hydrophilic spacer (i.e., PEG) attaches the lipophilic molecule to the branching molecule.
Wu et al teaches branched PEG chains in reaction scheme 7, which is the synthesis of 3-choloyl-l,2-bis(methoxyhexaethylenesuccinyl glycol)-3- cholate (see image in the above rejection).
More specifically, Wu et al teaches, “In accordance with the present invention, a pharmaceutical composition can include one or more genetic vectors, antisense molecules, proteins, peptides, bioactive lipids or drugs. For example, the active agent can include one or more drugs (such as one or more anticancer drugs or other anticancer agents). Typically hydrophilic active agents will be added directly to the formulation. . . Suitable active agents that can be present in the inventive formulation include one or more genetic vectors, antisense molecules, proteins, peptides, bioactive lipids or drugs, such as are described above. The inventive PEG-lipid can be used to administer active agents that are safer in presence of PEG oligomer for intravenous use.”, (para [065] to [066]).
Further, Wu et al teaches, “Suitable agents can be selected from, for example, . ., nucleotides, polynucleotides, . . . Active agents can be . . ., antisense oligonucleotides. . .”, (para [067]). “For in vivo use, the invention provides the use of a composition as herein described containing one or more active agents for preparing a medicament for the treatment of a disease. In other words, the invention provides a method of using a composition as herein described, containing one or more active agents, for treating a disease.”, (para [071).
Moreover, Wu et al teaches chemical structure 13 and that X and L are the same or different linkers, where n is the number of repeating units of PEG, and wherein terminal groups besides methyl may be included on the PEG chains (para [076]; image in the above rejection).
Wu et al teaches that “Embodiments of the present invention are described herein in the context of preparation of pharmaceutical compositions including purified PEG-lipid conjugates for increasing the solubility and enhancing the delivery of active agents. The approximate preferable compositions for formulated drug products are generally described herein, though different drugs typically have differing optimal formulations.”, (para [0077]).
Wu et al teaches, “Syntheses of polyethyleneglycol (PEG)-lipid conjugates are disclosed. Such syntheses involve stepwise addition of small PEG oligomers to a glycerol backbone until the desired chain size is attained. Polymers resulting from the syntheses are highly monodisperse. The present invention provides several advantages such as simplified synthesis, high product yield and low cost for starting materials. The present synthesis method is suitable for preparing a wide range of conjugates. In another aspect, the invention comprises PEG lipid conjugates having a glycerol backbone covalently attached to one or two monodisperse PEG chains and one or two lipids.”, (para [007] to [008]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of claim 2 of ‘644, i.e., an siRNA attached to a PEG45 attached to a branching molecule attached to two lipids, with the teachings of Wu et al, i.e., incorporating PEG oligomers after the branching point, to yield the predictable results a conjugate comprising an siRNA attached to a PEG45 attached to a branching molecule attached to PEG oligomers attached to the lipids individually. One would be motivated to do so because Wu et al teaches that branched PEG-Lipid conjugates: (a) are highly monodispersed, (b) simplify synthesis, (c) have a high yield, (d) have a low cost of starting material, (e) increase solubility, and (f) enhance the delivery of active agents. One could have looked to the teachings of both claim 2 of 644 and Wu et al, and combine, i.e., inserted the PEG after the branching point, and arrived at the claimed invention with a high-likelihood of success.
Instant claim(s) 1-6, 8-9, 13-16, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of 644 in view of Wu et al.
Claim 20 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of U.S. Patent No. 12,201,644 B2 in view of Wu et al (supra) as applied to claim(s) 1-6, 8-9, 13-16, and 18 above, and further in view of Chappell et al (supra).
Claim 2 of 644 in view of Wu et al does not teach wherein the conjugate has a binding affinity (Kd) to albumin of less than 1uM.
Chappell et al teaches, “Notably, the affinity for albumin, by far the most abundant plasma protein, increased 200-fold with conjugation of palmitate from 56 μM for ASO to 218 nM for Palm-ASO.”, (p. 4387, col 2, para 3).
Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to substitute the lipophilic molecules from the combination of claim 2 of 644 in view of Wu et al, with a palmitate as taught by Chappell et al to yield the predictable results of a conjugate having a binding affinity of less than 1uM. Palmitate is a known albumin binding lipid, and was known before the filing date. One of skill in the art would be motivated to utilize palmitate as the lipophilic ligand because Chappell et al teaches that Palm-ASO conjugates have a 218nM affinity to albumin. Thus, one of skill could look to the claim of 644 in view of Wu et al and the teachings of Chappell et al, and substitute the lipophilic ligand for palmitate and arrive at the claimed invention with a high likelihood of success.
Accordingly, instant claim 20 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of 644 in view of Wu et al in further view of Chappell et al.
Claim(s) 1-6, 8-9, 13-16, 18, and 26 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 6, 11, and 16 of copending Application No. 18/974,693 in view of Wu et al (supra).
Claim 6 of ‘693 recites, “The compound of “The compound of “A compound comprising a RNA directly conjugated to an albumin-binding group.”, wherein the albumin-binding group is a divalent lipidic moiety.”, wherein the divalent lipidic moiety comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] (L2).”
Claim 11 of ‘639 recites, “A compound comprising siRNA functionalized with a dibenzocyclooctyne moiety and directly conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000].”
Claim 16 of ‘639 recites, “The method of “A method of gene silencing, the method comprising administering a compound comprising a RNA directly conjugated to an albumin-binding group to a subject in need thereof.”, wherein the albumin-binding group comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] (L2).”
Claim(s) 6, 11, or 16 do not require wherein the hydrophilic spacer (i.e., PEG) attaches the lipophilic molecule to the branching molecule.
Wu et al teaches branched PEG chains in reaction scheme 7, which is the synthesis of 3-choloyl-l,2-bis(methoxyhexaethylenesuccinyl glycol)-3- cholate (see image in the above rejection).
More specifically, Wu et al teaches, “In accordance with the present invention, a pharmaceutical composition can include one or more genetic vectors, antisense molecules, proteins, peptides, bioactive lipids or drugs. For example, the active agent can include one or more drugs (such as one or more anticancer drugs or other anticancer agents). Typically hydrophilic active agents will be added directly to the formulation. . . Suitable active agents that can be present in the inventive formulation include one or more genetic vectors, antisense molecules, proteins, peptides, bioactive lipids or drugs, such as are described above. The inventive PEG-lipid can be used to administer active agents that are safer in presence of PEG oligomer for intravenous use.”, (para [065] to [066]).
Further, Wu et al teaches, “Suitable agents can be selected from, for example, . ., nucleotides, polynucleotides, . . . Active agents can be . . ., antisense oligonucleotides. . .”, (para [067]). “For in vivo use, the invention provides the use of a composition as herein described containing one or more active agents for preparing a medicament for the treatment of a disease. In other words, the invention provides a method of using a composition as herein described, containing one or more active agents, for treating a disease.”, (para [071).
Moreover, Wu et al teaches chemical structure 13 and that X and L are the same or different linkers, where n is the number of repeating units of PEG, and wherein terminal groups besides methyl may be included on the PEG chains (para [076]; image in the above rejection).
Wu et al teaches that “Embodiments of the present invention are described herein in the context of preparation of pharmaceutical compositions including purified PEG-lipid conjugates for increasing the solubility and enhancing the delivery of active agents. The approximate preferable compositions for formulated drug products are generally described herein, though different drugs typically have differing optimal formulations.”, (para [0077]).
Wu et al teaches, “Syntheses of polyethyleneglycol (PEG)-lipid conjugates are disclosed. Such syntheses involve stepwise addition of small PEG oligomers to a glycerol backbone until the desired chain size is attained. Polymers resulting from the syntheses are highly monodisperse. The present invention provides several advantages such as simplified synthesis, high product yield and low cost for starting materials. The present synthesis method is suitable for preparing a wide range of conjugates. In another aspect, the invention comprises PEG lipid conjugates having a glycerol backbone covalently attached to one or two monodisperse PEG chains and one or two lipids.”, (para [007] to [008]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of claim 2 of ‘644, i.e., an siRNA attached to a PEG45 attached to a branching molecule attached to two lipids, with the teachings of Wu et al, i.e., incorporating PEG oligomers after the branching point, to yield the predictable results a conjugate comprising an siRNA attached to a PEG45 attached to a branching molecule attached to PEG oligomers attached to the lipids individually. One would be motivated to do so because Wu et al teaches that branched PEG-Lipid conjugates: (a) are highly monodispersed, (b) simplify synthesis, (c) have a high yield, (d) have a low cost of starting material, (e) increase solubility, and (f) enhance the delivery of active agents. One could have looked to the teachings of both claim(s) 6, 11, or 16 of 693 and Wu et al, and combine, i.e., inserted the PEG after the branching point, and arrived at the claimed invention with a high-likelihood of success.
Instant claim(s) 1-6, 8-9, 13-16, 18 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 6, 11, and 16 of 693 in view of Wu et al.
This is a provisional nonstatutory double patenting rejection.
Claim 20 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 6, 11, and 16 of copending Application No. 18/974,693 in view of Wu et al (supra) as applied to claim(s) 1-6, 8-9, 13-16, 18, and 26 above, and further in view of Chappell et al (supra).
Claim(s) 6, 11, and 16 of 693 in view of Wu et al does not teach wherein the conjugate has a binding affinity (Kd) to albumin of less than 1uM.
Chappell et al teaches, “Notably, the affinity for albumin, by far the most abundant plasma protein, increased 200-fold with conjugation of palmitate from 56 μM for ASO to 218 nM for Palm-ASO.”, (p. 4387, col 2, para 3).
Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to substitute the lipophilic molecules from the combination of claim(s) 6, 11, and 16 of 693 in view of Wu et al, with a palmitate as taught by Chappell et al to yield the predictable results of a conjugate having a binding affinity of less than 1uM. Palmitate is a known albumin binding lipid, and was known before the filing date. One of skill in the art would be motivated to utilize palmitate as the lipophilic ligand because Chappell et al teaches that Palm-ASO conjugates have a 218nM affinity to albumin. Thus, one of skill could look to the claim(s) of 693 in view of Wu et al and the teachings of Chappell et al, and substitute the lipophilic ligand for palmitate and arrive at the claimed invention with a high likelihood of success.
Accordingly, instant claim 20 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 6, 11, and 16 of 693 in view of Wu et al in further view of Chappell et al.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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