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 .
Priority
The present application, filed July 8, 2022, is a national stage application of PCT/EP2021/050276, filed January 8, 2021, which claims priority to foreign priority application EP20305019.0, filed January 10, 2020.
Election/Restrictions
Applicant’s election of Group I, claims 1-5, 12, 13, 19, and 20, in the reply filed on September 23, 2025, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 6-10 and 14-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to the nonelected inventions of Groups II, III, IV, V, and VI, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 23, 2025.
Status of the Application
Claims 1-10 and 12-20 are pending.
Claims 6-10 and 14-18 are withdrawn as being directed to a non-elected invention.
Claims 1-5, 12, 13, 19, and 20 are examined on the merits herein.
Duplicate Claim Warning
Applicant is advised that should claims 12 and 13 be found allowable, claims 19 and 20 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Objections
Claim 5 is objected to because of the following informalities:
Claim 5 recites “wherein said carriers D”. The examiner believes this to be a typographical error and should recite “wherein said carrier D”.
Appropriate correction is required.
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.
Claims 1, 3-5, 12, 13, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Rathwell (U.S. pre-grant publication no. US 20160279224 A1; cited in restriction requirement mailed July 23, 2025) in view of Elewaut (Publication no. WO 2014001204 A1; cited in restriction requirement mailed July 23, 2025).
Claim 1 is drawn to an iNKT stimulator of formula II as defined in the claim. Claim 3 is drawn to a conjugate comprising at least one iNKT stimulator coupled to at least one carrier, wherein said conjugate has the structure of formula II. Claim 4 depends from claim 1 and requires the carrier D is a therapeutic agent and/or a targeting agent, and claim 5 depends from claim 1 and claims the carrier is specific type of compound recited in the claim. Claims 12 and 19 depend from claim 3 and require the carrier D is a therapeutic agent and/or a targeting agent, and claims 13 and 20 depend from claim 3 and claim the carrier is specific type of compound recited in the claim.
Rathwell teaches conjugates that may be used for immunization against diseases associated with Streptococcus pneumoniae (cover page, Abstract, lines 6-8). Rathwell teaches that the glycosphingolipid α-galactosyl ceramide, also known as KRN7000, has been identified as an immune activator that lowered the tumor burden of mice. Rathwell teaches that this glycosphingolipid is known to be presented by antigen presenting cells by loading onto the protein CD1d, and that after being loaded with the glycolipid, CD1d will interact with an invariant T-cell receptor (TCR) of invariant natural killer T cells (iNKT cells), resulting in the activation of the iNKT cells, expansion of their population, and secretion of cytokines (p. 1, [0005], lines 1-11). Rathwell teaches that immune responses have been observed by immunization of mice carrying antigens conjugated to NKT ligands, including a-galactosylceramide (p. 1, [0005], lines 16-27).
Rathwell teaches that the objective of their invention is a conjugate of general formula (I) comprising a Streptococcus pneumoniae type 3 capsular polysaccharide covalently linked to a glycosphingolipid, and that immunization with these conjugates results in the production of high titers of antibodies against pneumococcal capsular polysaccharide of SP3 (p. 1, [0006], lines 1-1).
As one example iNKT stimulator compound, Rathwell teaches the compound of Example C.3 (p. 64, [0372]), which satisfies all limitations of the present compound of formula (II) except for the required carbamate linkage between the galactosyl group and variable group X. This compound has the core structure of formula (II) with X as a C4 alkyl chain (having n as 4), R as -CO-R1-, R1 as –(CH2)q-R2 with q as 2, and with R2 as the functional reacting group maleimide, which allows for conjugation to a carrier D.
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Rathwell teaches this compound may be conjugated to core capsular polysaccharide (CPS) structures of Streptococcus pneumoniae, as defined in general formula I of their compounds and defined by variable groups A and B (p. 1, [0008]-[0011]). Rathwell further teaches that the carbohydrate structure may be conjugated using the maleimide group (see pp. 36-37, [0220]-[0221]), wherein the structure 44 (p. 37, [0221]) shows the maleimide orientation as embodied in the compound of Example C.3 above.
Rathwell does not teach a specific compound with the carbamate linkage between the galactosyl group and variable group X, as required by the compound of formula (II) recited in independent claims 1 and 3.
Elewaut teaches compounds that may be used as immunostimulating agents. Elewaut teaches that natural killer T (NKT) cells are a subset of T cells that recognize glycolipid antigens when presented by the major histocompatibility complex class I-like molecule CD1d and, when activated, result in immediate cytokine production, cytotoxicity, and proliferation, which subsequently activates by-stander immune cells (p. 1, lines 16-25). Elewaut teaches that the most well-studied CD1d-presenting antigen that specifically activates iNKT cells is α-GalCer, known as KRN7000 (p. 1, lines 26-28).
Elewaut teaches that when NKT cells are activated, Th1 and Th2 cytokines are released (p. 2, lines 6-8). Elewaut further teaches that Th1 cytokines are thought to mediate the antitumor, antiviral, and antibacterial effects of α-GalCer (p. 2, lines 25-26).
Elewaut teaches that to explore the relationship between 6”-substituted α-GalCer analogues and Th1-biased activity, they prepared and evaluated a series of novel carbamate, thiocarbamate, and triazolyl derivatives of α-GalCer (p. 6, line 31 to p. 7, line 2). Elewaut teaches that these glycolipids showed an increased stability to CD1d compared to α-GalCer (p. 7, line 2). Elewaut teaches that their 6” carbamate derivatives are also able to stimulate human iNKT cells (p. 7, lines 8-9).
As examples, Elewaut teaches galactosyl derivative compounds modified with pyridyl and 4-Cl-phenyl groups (document p. 85, Figure 1; structures shown below). These compounds satisfy all limitations of the compound of formula (II) of present claims 1 and 3 except for the required substituent of X and groups attached to X in the compounds of formula (II).
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Elewaut concludes by stating that their invention is based on the unexpected finding that galactopyranosyl derivatives with carbamate, thiocarbamate, or triazolyl moieties exhibit enhanced biological activities (p. 7, lines 16-19) (emphasis added).
It would have been prima facie to obvious to one of ordinary skill in the art before the effective filing date of the present application to modify the compound of example C.3 taught by Rathwell and substitute the -O-C- linkage between C6 of the galactosyl group and presently defined variable group X with a carbamate group, as present in the iNKT activators taught by Elewaut. One of ordinary skill in the art would have been motivated to modify example C.3 taught by Rathwell and substitute the -O-C- linkage between C6 of the galactosyl group and variable group X with a carbamate group, as present in the iNKT activators taught by Elewaut, because Elewaut teaches that their compounds featuring carbamate linkages are also able to stimulate human iNKT cells. In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Rathwell teaches compounds that present Streptococcus pneumoniae carbohydrates that may be used to activate iNKT cells for the purposes of immunizing subjects against pneumococcal polysaccharides, and because Elewaut teaches structurally related compounds with carbamate linkages that also activate iNKT cells, one of ordinary skill in the art would have reasonably considered modifying example C.3 of Rathwell by substituting the -O-C- linkage from C6 of the galactosyl group with the carbamate group taught by Elewaut, because such a compound, when conjugated to the Streptococcus pneumoniae carbohydrates taught by Rathwell, would also be expected to also activate iNKT cells and provide immunization against pneumococcal polysaccharides.
One of ordinary skill in the art would have had a reasonable expectation of success modifying example C.3 of Rathwell with the carbamate linkage, as taught by Elewaut, because each of Rathwell and Elewaut teach their compounds as useful for activating iNKT cells, and thus one of ordinary skill in the art would have had a reasonable expectation that modifying the compound of Rathwell with a carbamate group would, when conjugated to the Streptococcus pneumoniae carbohydrates taught by Rathwell, successfully activate iNKT cells and provide immunization against the pneumococcal polysaccharides taught by Rathwell.
Regarding the therapeutic and/or targeting agent recited in claims 4, 12, and 19 and the specific carrier D recited in claims 5, 13, and 20, because the Streptococcus pneumoniae carbohydrates may be used for immunization against diseases associated with Streptococcus pneumoniae by raising antibodies to said carbohydrates, as taught by Rathwell, it is reasonably considered as a therapeutic agent because bacterial and viral antigens are recited in the specification as exemplary therapeutic agents (p. 17, lines 22-24). In addition, because the Streptococcus pneumoniae carbohydrates are carbohydrates, it also satisfies the limitations of claims 5, 13, and 20.
Therefore the invention taken as a whole is prima facie obvious.
Claims 1, 3-5, 12, 13, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Seeberger (U.S. pre-grant publication no. US 20150238597 A1; cited in PTO-892) in view of Elewaut.
Seeberger teaches methods of preparing and evaluating carbohydrate-based vaccines (cover page, Abstract, lines 1-3). Seeberger teaches that protection against an infectious disease is provided by neutralization of virulence factors or opsonizing antibodies, and that these antibodies must be directed against the carbohydrate antigen of the pathogen, e.g. from capsules composed of polysaccharides or viral glycoproteins. Seeberger teaches that an ideal efficient vaccine has to induce high affinity and complement-fixing anti-carbohydrate antibodies, which is
fulfilled by the conjugates of their invention (p. 1, [0012], lines 1-8).
Seeberger specifically teaches compound 40 (p. 61, compound 40). This compound has the core structure of formula (II) with X as a C4 alkyl chain (having n as 4), R as -CO-R1-, R1 as –(CH2)q-R2 with q as 3, and with R2 as the functional reacting group carboxylic acid, which allows for conjugation to a carrier D.
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Seeberger further teaches that other structurally related compounds, including compound 27b (p. 60, structure shown in [0274]) were conjugated to PS4 and showed immunogenic activity (p. 61, [0128]). PS4 is an antigenic capsular polysaccharide portion (p. 62, [0284], lines 1-2) and is interpreted herein as both a therapeutic agent and a carbohydrate, as recited in claims 4, 5, 12, 13, 19, and 20.
Seeberger does not teach a compound with the carbamate linkage between the galactosyl group and variable group X, as required by the compound of formula (II) recited in independent claims 1 and 3.
Elewaut teaches as described in the above rejection under 35 U.S.C. 103.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify compound 40 of Seeberger and substitute the -O-C- linkage between C6 of the galactosyl group and presently defined variable group X with a carbamate group, as present in the iNKT activators taught by Elewaut. One of ordinary skill in the art would have been motivated to modify compound 40 by Seeberger and substitute the -O-C- linkage between C6 of the galactosyl group and variable group X with a carbamate group, as present in the iNKT activators taught by Elewaut, because both Seeberger and Elewaut teaches that their compounds are able to stimulate human iNKT cells. In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Seeberger teaches compounds that present an antigenic capsular polysaccharide for the purposes of preparing carbohydrate-glycolipid conjugate vaccines which are capable of stimulating immunogenicity, and because Elewaut similarly teaches glycolipids with carbamate linkages that activate iNKT cells, one of ordinary skill in the art would have reasonably considered modifying compound 40 of Seeberger by substituting the -O-C- linkage from C6 of the galactosyl group with the carbamate group taught by Elewaut, because such a compound, when conjugated to an antigenic capsular polysaccharide taught by Seeberger, would also be expected to stimulate immunogenicity via activation of iNKT cells.
One of ordinary skill in the art would have had a reasonable expectation of success modifying compound 40 of Seeberger with the carbamate linkage, as taught by Elewaut, because each of Seeberger and Elewaut teach their compounds as useful for stimulating immunogenicity, and thus one of ordinary skill in the art would have had a reasonable expectation that modifying the compound of Seeberger with a carbamate group would, when conjugated to the antigenic capsular polysaccharide taught by Seeberger, also stimulate an immunogenic response to said polysaccharide.
Regarding the therapeutic and/or targeting agent recited in claims 4, 12, and 19 and the specific carrier D recited in claims 5, 13, and 20, because the antigenic capsular polysaccharide may be used to stimulate an antigenic response, as taught by Seeberger, it is reasonably considered as a therapeutic agent because bacterial and viral antigens are recited in the specification as exemplary therapeutic agents (p. 17, lines 22-24). In addition, because the antigenic capsular polysaccharide is a carbohydrate, it also satisfies the limitations of claims 5, 13, and 20.
Therefore the invention taken as a whole is prima facie obvious.
Allowable Subject Matter
Claim 2 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 2 depends from claim 1 and requires the iNKT stimulator is a structure of formula (V), (VI), (VII), and (VIII). The closest prior art to these compounds is considered Max-Planck (Publication no. EP2851092A1; cited in PTO-892). Max-Planck teaches compound 34**a (p. 46, [0136]; structure reproduced below).
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This compound differs from the presently claimed compounds in that the galactose group is glucose, the compound lacks a carbamate functional linking the glucose moiety to the PEG group, and because the amino group is not acylated, as required by the compounds of claim 2. Although substitution of glucose for galactose and introduction of the carbamate group would have been obvious over combinations of Rathwell, Elewaut, Seeberger, and Max-Planck using the rationales described in the above rejections, none of these references teach or suggest acylation of the amino group of compound 34**a to form the compound of formula (V) or (VI). In addition, none of these references teach or suggest acylation of compound 34**a with a maleimide-modified PEG group to form the compounds of formulas (VII) or (VIII).
Moreover, Wang (U.S. pre-grant publication no. 20090275483 A1; cited in the IDS received April 19, 2024) teaches the same compound as Max-Planck above (document p. 2, Figure 1, compound 1), but uses the amino group to anchor the compound to a glass slide substrate for the purposes of studying the interaction between galactosyl ceramide and its biological target (p. 17, [0051]), and thus one of ordinary skill in the art would not have been motivated to acylate the amine with the groups required by claim 2 to form compounds of formulas (V), (VI), (VII), or (VIII).
Conclusion
Claims 1, 3-5, 12, 13, 19 and 20 are rejected.
Claim 2 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN BRANDSEN whose telephone number is (703)756-4780. The examiner can normally be reached Monday - Friday from 9:00 am to 5:00 pm.
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/B.M.B./Examiner, Art Unit 1693
/ERIC OLSON/Primary Examiner, Art Unit 1693