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
Claims 1-7, 9-12 and 15-25 and 27-39 are currently pending
Claims 32-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/03/2025.
Claims 3, 7, 9, 11, 23, 36 and 39 are withdrawn and claims from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 06/03/2025.
1-2, 4-6, 8, 10, 12, 15-22, 24-25, 27-31, 35, 37-38 are under consideration.
Rejections/Objections Withdrawn
Claim Objections
The objections to claims 4 and 30 are withdrawn in view of claim amendments.
Rejections Maintained
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 20 contains the trademark/trade name “Montanide”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an adjuvant molecule and, accordingly, the identification/description is indefinite.
Response to Arguments
Applicant's arguments filed 9/26/2025 have been fully considered but they are not persuasive.
Applicant argues that the term “Monatinide ISA 51VG” is registered with the FDA DMF, its composition is known and the term would be readily understood by one of skill in the art. In response, the following is an excerpt from MPEP § 2173.05(u):
If the trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). See also Eli Lilly & Co. v. Apotex, Inc., 837 Fed. Appx. 780, 784-85, 2020 USPQ2d 11531 (Fed. Cir. 2020) ("Following Patent Office procedure, the Examiner in this case rejected the claims of the '821 application as indefinite because they improperly used the trade name 'ALIMTA.' In response to the rejection, Lilly canceled its claims reciting the trade name and pursued claims using the generic name for the same substance, which mooted the rejection. Additionally, as the district court observed, the Examiner 'explicitly noted that pemetrexed disodium was 'also known by the trade name ALIMTA' ' in the contemporaneous obviousness rejection."). The claim scope is uncertain since the trademark or trade name cannot be used properly to describe any particular material or product. In fact, the value of a trademark would be lost to the extent that it became the generic name of a product, rather than used as an identification of a source or origin of a product. Thus, the use of a trademark or trade name in a claim to describe a material or product would not only render a claim indefinite, but would also constitute an improper use of the trademark or trade name. If the applicant responds to such a rejection by replacing the trademark or trade name with a generic term, the examiner should determine whether there is sufficient support in the application for use of a generic term. See MPEP § 2163, subsection II.A.3(b).
In the example above, the trade name “ALIMTA” recited as a limitation directed toward a product was improper despite the examiner acknowledging frequent use of the trade name in the art. As such, demonstrating that a trade name is in use and/or understood in the art is not sufficient to overcome this 35 USC § 112(b) rejection.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 4-6, 8, 10, 12, 15-22 and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Poudel (Poudel, et al., WO 2019/035968 A1; Published 02/21/2019, of record) in view of Chan (Chan, et al., Bioconjugate Chem. 2011 22:445, of record).
Poudel teaches on the subject of 6-amino-7,9-dihydro-8H-purin-8-one derivatives as TLR7 agonists and immunostimulants (Poudel, Abstract). Poudel teaches that activation of TLR7 by an agonist has adjuvant effects on the action of vaccines in treating conditions other than pathogen infection via such TLR7 activation stimulating an immune response (Poudel, ¶ 0004). Poudel teaches that synthetic TLR7 agonists frequently comprise the purine-like scaffold below (Poudel, ¶ 0008):
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Additionally, Poudel teaches that purine-like molecules are biologically active and useful for treating both cancer and pathogenic infection (Poudel, ¶ 0009), that the R’’ group in the structure above is permitted to be pyridyl (Poudel, ¶ 0010) and that TLR7 agonists conjugated to polyethylene glycol (“PEG”) were known in the art at the time (Poudel, ¶ 0012). Moreover, Poudel teaches that the presence of secondary alkyl amines on the TLR7 agonists of Poudel are particularly useful, as they provide attachment sites for linkers (Poudel, ¶ 00113). Poudel teaches that one of the specific compounds of Poudel is Compound Ic-08, which is depicted next to the elected species below for comparison:
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Please note that Compound Ic-08 and the elected species exhibit keto/enol tautomerism, with Poudel’s Compound Ic-08 being depicted in enol form and the elected species being depicted in the keto form. Note that the only differences between compound Ic-08 and the elected species are limited to the linear moiety extending from the pyridine ring. As such, Compound Ic-08 of Poudel reads on all of the structural limitations of all of the claims with the exception of limitations regarding the Y1 moiety.
Poudel does not teach Compound Ic-08 of Poudel, wherein there is a linear PEG4-OH moiety attached to the pyridine ring via a tertiary amino moiety.
Chan teaches on the subject of PEGylated TLR7 ligands (Chan, Abstract). Chan teaches that the TLR7 agonist 1V136 is highly insoluble in water and this motivated Chan to attach hydrophilic PEG chains, which did increase the water solubility of the ligand, with longer PEG chains providing greater solubility (Chan, p 448, ¶ 11). Please note that the structure of 1V136 is found above Table 1, which is found on p 449 of the Chan reference and 1V136 is virtually identical to the elected species if the L and Y1 groups are absent except for two difference: 1) the aromatic ring attached to the purine-like scaffold is phenyl in the Chan reference but pyridine in the elected species and 2) the second to last atom of the linear moiety extending from the 6-member ring of the purine-like moiety is oxygen in the Chan reference but carbon in the elected species. Chan teaches that relationship between PEG chain length and biological effects is nonlinear, with molecules comprising short PEG polymers having lower induction of proinflammatory cytokines compared to the free drug and despite improved circulation time, while longer PEG polymers exhibited higher induction of said cytokines (Chan, p 452, ¶ 3- 453, ¶ 6. This effect was observed up to a point, however, with the molecule having the longest PEG chain (472 PEG units) having the highest EC50 for NFkB of all the molecules tested (Chan, Table 2).
It would be prima facie obvious to one of ordinary skill in the art to modify compound Ic-08 of Poudel to comprise a linear PEG4-OH moiety attached to the pyridine ring via a tertiary amino moiety in view of the teachings of Chan. One of ordinary skill in the art would be motivated to do this in order to better increase the in vivo immunostimulatory properties of Ic-08. Poudel teaches that the secondary amine group attached to the pyridine ring provides a suitable means to attach a linker (such as a PEG4 OH linker) to the TLR7 ligand. The teachings of Chan show that the relationship between specific immunostimulatory properties and PEG chain length is a complex relationship, which provides sufficient teaching and motivation for one of skill in the art to realize that such a problem can only be solved empirically. Adding PEG chains of differing lengths to molecules and observing the effects is very routine in the art, is a matter of routine experimentation and within the purview of one of skill in the art. One of ordinary skill in the art would have a reasonable expectation of success starting with compound Ic-08 of Poudel and arriving at the compound comprising the instant claimed PEG4 polymer via routine experimentation because the teachings of Chan demonstrate that there are multiple factors at play with respect to the relationship between PEG polymer length and net in vivo immunostimulatory effect coupled with the fact that changing the number of repeat units in a PEG polymer and observing results is very routine in the art. Additionally, although not absolute, the Chan paper teaches in that in general and at these levels, increasing the length of the PEG chain results in overall higher adjuvant activity. The elected species comprises a slightly longer PEG chain than Compound Ic of Poudel and this is not unexpected in view of the overall teachings of Chan.
Additionally, in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F. 2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) See MPEP 2144.05. Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP 2144.05(11).
Additionally, the terminal Boc group present in Poudel’s Ic-08 is an amine protecting group that is removed to yield an amine group just prior to transglutaminase-mediated conjugation (see ¶ 00159-00161 of Poudel) to an antibody. Since this would not be necessary for a small molecule vaccine adjuvant there would naturally be a hydroxyl group in that position given the orientation of the PEG coupled with the fact that it is the terminal repeat unit.
Response to Arguments
Applicant's arguments filed 9/26/2025 have been fully considered but they are not persuasive.
Applicant argues that the Poudel reference discloses TLR7 agonists but does not provide data showing adjuvant activity or describe structural modifications. Applicant then argues that the Chan reference is outside of the scope of the current claims and that Chan fails to disclose adjuvant activity of some of the higher order PEG TLR7 agonists of Chan and that Chan teaches that lower order PEG may demonstrate partial or attenuated agonist activity.
In response, Applicant is reminded that the differences between the elected species under examination and Poudel are very, very minimal:
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The Chan reference was applied to show why one of ordinary skill in the art would be motivated to vary PEG repeat groups in compound Ic-08 of Poudel to arrive at a PEG4 group instead of the PEG3 group taught by Poudel. The Chan paper is nearly entirely on the subject of varying the compositions of PEG components attached to similar but yet structurally distinct TLR7 agonists and noting the pertinent immunological changes when the PEG number is varied. Varying PEG repeat unit numbers is very, very routine in the art and it is within the purview of one of skill in the art to vary the PEG lengths of compound Ic-08 of Poudel just like Chan varied the PEG lengths of the TLR7 agonists of Chan.
Applicant also makes several arguments alleging unexpected results. Applicant cites data from Example 3, Example 2, Example 6 and Example 7. Demonstration of unexpected results can rebut an allegation of prima facie obviousness (See MPEP § 716.02(a)). However, all of the data presented do not contain controls sufficient to demonstrate unexpected results. All of the Tests compare one of the instant claimed PEGylated TLR7 agonists to simply to the non-PEGylated version of the same TLR7 agonist. Demonstrating that this particular class of molecule performs better when conjugated to PEG chains are very, very expected results in view of the teachings of Chan. In order to overcome such a prima facie case of obviousness, Applicant would need to demonstrate the instant claimed TLR7 agonists perform unexpectedly better than what one of ordinary skill in the art would expect the TLR7 agonists of Poudel to perform with one additional PEG group, and those data must be commensurate with the scope of the claims (See MPEP § 716.02(d)).
Claim(s) 1-2, 4-6, 8, 10, 12, 15-22, 24-25, 27-31, 35 and 37-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Poudel (Poudel, et al., WO 2019/035968 A1; Published 02/21/2019, of record) in view of Chan (Chan, et al., Bioconjugate Chem. 2011 22:445, of record) as applied to claims 1-2, 4-6, 8, 10, 12, 15-22 and 24 above and in further view of Li (Li, et al., US 9,181,302 B2; Issued 11/10/2015, of record) and Sammatur (Sammatur, et al., CA 3069019; Published 1/17/2019, of record).
The teachings of Poudel and Chan are discussed above.
The combined teachings of Poudel and Chan do not teach a pharmaceutical composition comprising the TLR7 agonist collectively taught by Poudel and Chan and further comprising a peptide comprising the sequences CRMFPNAPYL and CYTWNQMNL, wherein the two peptides are linked by a disulfide bond. The combined teachings of Poudel and Chan do not teach that the pharmaceutical composition is formulated in cholesterol/phospholipid liposomes in a Montanide ISA 51 water-in-oil emulsion.
Li teaches of a cancer immunotherapy that is a conjugate vaccine obtained by linking peptide precursors from WT1 antigen protein via a sulfur-sulfur bond and that this conjugate vaccine efficiently induces cytotoxic T cells to attack cancer cells (Li, column 1, lines 16-39). Li also teaches that the disulfide conjugate peptide of Li consists of peptides having the sequences of CRMFPNAPYL and CYTWNQMNL, wherein the two peptides are linked by a disulfide bond (Li, claim 2).
Sammatur teaches on the subject of methods of preparing a dried preparation comprising lipids and therapeutic agents (Sammatur, ¶ 0002). Sammatur teaches that formulations comprising multiple different therapeutic agents within a single composition is a time consuming and labor-intensive process when some of the therapeutic agents possess a high degree of hydrophobicity (Sammatur, ¶ 0004) and that this is of particular relevance for personalized peptidic cancer vaccines where timing is critical and poses significant hurdles and wherein vaccines deliver 10-30 individual peptides (Sammatur, ¶ 0005- 0006). Sammatur teaches that the method of Sammatur comprises: 1) providing lipid vesicle particles of an average diameter of <= 120 nm, 2) mixing the lipid vesicle particles to form a mixture and 3) drying that mixture to form a dried preparation comprising lipid and a therapeutic agent (Sammatur, ¶ 0043). Sammatur teaches that the lipid vesicle particles of Sammatur are liposomes that are in the range of 80-120 nm with a polydispersity index of <= 0.1(Sammatur, ¶ 0062-0063). Sammatur teaches that the dried lipid/therapeutic agent preparation of Sammatur was prepared by mixing DOPC, cholesterol and sodium phosphate (an inorganic acid salt; see claim 31) to form lipid vesicle particles and then mixing in a dIdC oligonucleotide adjuvant, a Y9T antigenic peptide and a A16L T helper peptide and then freeze dried (Sammatur, ¶ 00647). Sammatur teaches that the dried product is then solubilized in Montanide ISA 51 (note: Montanide ISA 51 is a water-in-oil emulsion itself) (Sammatur, ¶ 00650).
It would be prima facie obvious to one of ordinary skill in the art to combine the purine-like scaffold comprising TLR7 adjuvant collectively taught by Poudel and Chan with the disulfide comprising the disulfide conjugate peptide of Li (same as instant Formula 4) and formulate this composition in the DOPC/cholesterol liposome/Montanide ISA 51 formulation of Sammatur. One of ordinary skill in the art would be motivated to do this in order to stimulate the immune system against the WT1 cancer antigens of Li with the largely hydrophobic adjuvant collectively taught by Poudel and Chan in a formulation suitable for hydrophobic molecules as well as multiple antigenic peptides. The TLR7 agonist collectively taught by Poudel and Chan is an adjuvant, meaning it is capable of enhancing an immune response against an antigen but is not an antigen itself. The disulfide-comprising conjugate peptide of Li is itself antigenic and Li teaches that administering the disulfide-comprising conjugate peptide of Li efficiently induces an immune response that attacks cancer cells. Pairing such an antigen with an adjuvant makes sense because a skilled artisan would envision that the adjuvant would enhance this immune response against cancer cells. The resultant composition comprises multiple peptides as well as a therapeutic agent that is hydrophobic. The formulation method taught by Sammatur was specifically designed for complex formulations involving multiple peptides as well as therapeutic agents that are hydrophobic and the method was designed to be robust and reliable. One of ordinary skill in the art would have a reasonable expectation of success combining the TLR7 adjuvant collectively taught by Poudel and Chan with the disulfide-comprising the disulfide conjugate peptide of Li (same as instant Formula 4) and formulate this composition in the DOPC/cholesterol liposome/Montanide ISA 51 formulation of Sammatur because: 1) the disulfide-comprising conjugate peptide of Li is antigenic and efficiently induces CTLs to attack cancer cells, 2) the TLR7 agonist collectively taught by Poudel and Chan is an adjuvant, which enhances the effect of such immune responses but is largely hydrophobic and 3) the liposome/Montanide formulation taught by Sammatur was specifically designed for formulating compositions comprising multiple peptide and hydrophobic elements.
Response to Arguments
Applicant did not file any remarks pertinent to this rejection except for stating that neither Sammatur nor Li remedy the alleged deficiencies of Poudel and Chan, which have been addressed above.
Conclusion
Claims 1-2, 4-6, 8, 10, 12, 15-22, 24-25, 27-31, 35, 37-38 are rejected.
No claims are allowed.
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 SYDNEY VAN DRUFF whose telephone number is (571)272-2085. The examiner can normally be reached 8 am - 5 pm.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643