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
Applicant’s election of Group I (claims 1-2, 6, 9-10, 20, and 24) in the reply filed on August 14, 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Claims 29-30, 34-36, 39, 42-44, 50, and 59-61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 August 14, 2025.
Status of Claims
Claims 1-2, 6, 9-10, 20, 24, 29-30, 34-36, 39, 42-44, 50, and 59-61 are currently pending. Claims 1-2, 6, 9-10, 20, and 24 are under examination and claims 29-30, 34-36, 39, 42-44, 50, and 59-61 are withdrawn pursuant to 37 CFR 1.142(b) above.
Claim Interpretation
Pursuant to MPEP 2111.01 IV, “or” is interpreted herewith as encompassing one, more than one, or all of the group members present, unless the context dictates otherwise, as set forth in the specification on pg. 72 in lines 4-10. The scope of claim 1 is interpreted as including embodiment (i), embodiment (ii), and embodiments (i) and (ii) in the same composition. The scope of claim 6 is interpreted as encompassing a sortase recognition sequence at the N-terminus alone, at the C-terminus alone, and at both the N- and C-terminus. However, the linker of claim 9 is interpreted as being only one of a hydrolysable linker and non-hydrolysable linker, because the context, as would be reasonably interpreted by one of ordinary skill, indicates that the embodiments are mutually exclusive of each other.
Additionally, “a”, “an”, and “the” are interpreted as including the plural referent (specification pg. 72 in line 3).
Specification
The use of the term “nanobody”, which is a trade name or a mark used in commerce, has been noted in this application. 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.
See Title and specification on pg. 1 in lines 5 and 7, pg. 7 in line 12, pg. 16 in line 32, pg. 48 in line 27, pg. 67 in line 34, pg. 68 in line 8 and 24, and pg. 69 in line 1.
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.
Claims 1-2, 6, 9-10, 20, and 24 are 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 1 is indefinite because different skilled artisans would arrive at different interpretations of part (i). Part (i) recites a composition comprising a conjugate comprising a VHH conjugate to an antigen and an anti-inflammatory agent. Some skilled artisan would argue that the claim requires that the anti-inflammatory agent is, in addition to the antigen, also conjugated to the VHH. Other skilled artisans would argue that the scope of claim 1 encompasses embodiments wherein the anti-inflammatory agent is not structurally bound to the VHH. Rather, the composition may comprise both a component A and a component B, wherein A is a VHH conjugated to an antigen and B is an inflammatory agent.
For the same reasons claim 10 is also indefinite for reciting “a single domain antibody (VHH) conjugated to an antigen and an anti-inflammatory agent.”
For the purposes of applying art, claim 1(i) and claim 10 are interpreted as encompassing both embodiments, i.e. the anti-inflammatory agent may be conjugated to the VHH or may be a structurally separate component of the composition.
Claims 2, 6, 9, 20, and 24 are rejected by virtue of their dependency on claim 1.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2 and 10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification is insufficient to establish possession of the full scope of the genus of VHH antibodies that bind to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., binding to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80), claiming antibodies with specific properties, e.g., binding to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80, can result in a claim that does not meet the written description requirement even when the polypeptide sequence of MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80 bound by the VHH antibody is known, because antibodies with those properties have not been adequately described. See Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Similar to the ruling in Reagents of the University of California v. Eli Lilly, the court in Amgen Inc. v. Sanofi reinforced that disclosure of an antigen by its structure and/or properties does not provide an adequate written description of an antibody claimed without more than the property of binding to said antigen. "[K]nowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies[.]" See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017). ( MPEP § 2163 II. 3(a)).
MPEP § 2163 instructs that the “’written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice…reduction to drawings…or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus…’ See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that ‘only describe[d] one type of structurally similar antibodies’ that ‘are not representative of the full variety or scope of the genus.’).”
No structures of VHH antibodies binding to DEC205, CD103, or CD1a were found in the specification or available in the art at the time of instant filing. A single anti-MHCII and anti-CD11c VHH antibody is disclosed in the specification on pg. 19 in Table 1. No structures of VHH anti-DC-SIGN, anti-CLEC9a, anti-CX3CR1, and anti-F4/80 are disclosed in the specification, and the art does not disclose a sufficient number of species to be representative of the diversity of structures encompassed by the claimed genera (see US 2011/0212168 A1 in ¶ [0017] on pg. 2, attached herewith, regarding anti-DC-SIGN VHH; JP 2019506867 A, attached herewith, regarding anti-CLEC9a VHH; US 2013/0224224 A1 in ¶’s [0170] through [0174] on pg. 4, attached herewith regarding anti-CX3CR1 VHH; and RU 2599423 C1 see Abstract as cited from English Translation, attached herewith, regarding anti-F4/80 VHH).
Therefore, the instant “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
The instant specification provides no working examples of VHH structures beyond the disclosed single species of anti-MHCII and anti-CD11c. The functional requirement that the antibody of the claimed method be capable of binding to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80 is merely a wish or plan for an agent which fails to satisfy the written description requirement because “antibodies with those properties have not been adequately described.” Centocor, 636 F.3d at 1352.
In considering whether the disclosed antibodies could be representative of the entire scope of the claimed genus, the following art applies:
Edwards et al. (J Mol Biol. 2003. 334: 103–118, cited herewith) generated over 1000 antibodies with 568 unique CDR3s identified, all against that same target, the B-lymphocyte growth factor known as “BLyS”, wherein 500 antibodies inhibited BLyS activity (see Abstract). Edwards describes in detail how the breadth of antibody structures against a given immunogen can be influenced by the immunization and/or selection methods (see Discussion Section).
Like Edwards, Lloyd et al. shows a repertoire of 1x1011 human antibody variable regions can generate large numbers of structurally unique, biologically active scFvs against a variety of polypeptide targets (see Protein Engineering, Design & Selection. 2009. 22(3): 159–168, 2009, e.g., at page 161-62 bridging paragraph and in Table 1, cited herewith).
As yet another example to illustrate the potential scope of the genus of antibodies encompassed by the instant claims, consider the teachings of Meyer et al. (British Journal of Haematology. 2018. 180: 808–820, cited herewith). Meyer describes the core binding region of the well-known anti-CD20 antibody rituximab corresponds to amino acid residues 170-ANPS- 173, wherein N171 is the key residue for binding. By contrast, the OBZ and B1 anti-CD20 antibodies share an overlapping epitope with rituximab (170-ANPSEKNSP-178); however, in contrast to rituximab residues at positions 176–178 contribute the most to binding (see page 809, left col., 2nd full paragraph). Meyer also described the production and characterization of a panel of new anti-CD20 antibodies which were shown to bind epitopes contained within or nearby the rituximab 170-ANPS-173 epitope but to bind to different residues than rituximab binds in this region (see page 811, “New CD20 mAbs with overlapping, but distinct epitopes,” see also page
815-16 bridging paragraph).
Camelid VHH antibodies are similar to a convention VH domain with remarkable differences in framework 2 (FR2) and CDR3, wherein CDR3 is, on average, longer than in VH and often has an inter-CDR disulfide bond (Nguyen. EMBO J. 2000. 19(5):921-930, cited herewith; pg. 921, “Introduction”). Nguyen’s investigations on variable domains of VHH sequences considered structures from the N-terminus to the Cys92 of FR3 (see pg. 922, right col. first para). CDR3, however, contributes to the most structural variation as due to increased incidences of recombination on account of containing diversity and joining recombination and somatic hypermutation (Bedouelle et al. FEES J. 2006 Jan;273(1):34-46, cited herewith; pg. 35, left col. last para). The combinations of loop conformations for loop sites overlapping CDR1 and 2 have 10 different combinations, compared to the matched camel conventional antibodies which have six loop conformation combinations (pg. 923, left col, last para spanning right col. in paras 1-2). As with conventional antibodies, somatic hypermutation contributes to the diversity of VHH structures with the highest variability in CDR1 and CDR2. (pg. 923, right col. in 4th and 5th para). VHH antibodies have an addition hypervariable region toward the N-terminus, Id. Similarly, four regions of nucleotide insertion or deletion with respect to germline sequences were found (pg. 923, right col., last para through pg. 925, left col.; see also Fig. 2 on pg. 924). Adding additional variation to VHH sequences over conventional VH’s, VHH’s have twice as many recombination signal sequences. Id. In conclusion, the portion of the variable domain comprising FR1-CDR2-FR2-CDR3-FR3, without consideration of CDR3 which is known to have a greater variability in length in VHH, VHH antibodies demonstrated a substantially higher amount of structural diversity than their convention counterpart.
In conclusion, even if multiple antibodies bind epitopes within the same small region of a given polypeptide it is not uncommon for said antibodies to bind to different amino acids even within said small region and for said antibodies to have structurally dissimilar CDRs. Therefore, in light of the breadth of structural diversity of antibodies that can bind within the same region and/or inhibit activity of their target, a person of ordinary skill in the art would not recognize that Applicant reasonably has possession of the full scope of VHH antibodies that bind to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80, particularly in view of the fact that VHH antibody structures may be more diverse than conventional antibodies. Applicant has only disclosed the structure of only one species of anti-MHCII and one species of anti-CD11c VHH antibodies without showing a number of species that are representative of the scope of the claimed genera. Likewise, the knowledge in the prior art does not exemplify / disclose VHH antibodies that bind to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80 antibodies sufficient to represent the breadth of antibodies encompassed by the instant claims. Therefore, there is also no disclosure of a representative number of species describing the claimed genus in the art that would lead one of skill to believe that Applicant possessed the full scope of the claimed antibodies.
As to whether there is a known structure-function correlation that would disclose the genus of VHH antibodies that bind to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80, consider that there is little predictability between the structure of an antibody’s binding site and the function of binding to a particular antigen.
Bedouelle et al. examined the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a > 100 fold drop in the “off rate” for ligand dissociation (Bedouelle et al., pg. 38-39; see Table 2). Bedouelle suggests that some mutations had a direct effect on antigen binding while others indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section).
Vajdos et al. (J Mol Biol. 2002. 320: 415-428, cited herewith) demonstrates that, with the sequence of an antigen and/or epitope alone, one could not show what structural features of an antibody are necessary for the purpose of binding to the target. Briefly, Vajdos et al. performed shotgun scanning mutagenesis to characterize the how the amino acids of the binding site contributed to the structure and function of the antibody (see, for example, last paragraph of pg. 416 bridging 417). However, to determine which antibody residues where responsible for binding to the target Vajdos et al. had to map mutagenesis results to the crystal structure of the antigen bound to the antigen binding site (see pg. 417, Fig. 4, pgs. 421-422, and pg. 423, right column, last full paragraph “[a]ccurate definition of the structural-binding epitope can only be achieved with an antibody-antigen co-crystal structure”). In light of Vajdos et al., the art demonstrates that antibody structure-function correlation is not established by the disclosing the characteristics of the antigen alone.
Given that the nature of VHH antibodies is similar to the nature of conventional antibodies with respect to CDR hypervariability and necessitating a combination of CDRs to bind to an epitope, one of ordinary skill in the art would have been able to reasonably apply, to VHH antibodies, the concepts regarding unpredictability of making changes to regions of hypervariability (e.g. CDRs) described in Bedouelle and Vajdos. That said, one of skill could have extrapolated from the teachings of Nguyen, regarding the addition combinations of CDR-adjoining loop structures and the additional site for hypermutation, to conclude that there is an even greater amount of variability in VHH structures than in convention VH domains. Therefore, there is no correlation between structure and function running through the class of molecules considered as “antibodies” in which VHH antibodies lie. Thus, one could not assume that the limited number of structures disclosed in the specification and/or art would have instructed the skilled artisan on what structures would result in the claimed property of binding to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80, therefore there is no correlation between the sequences laid forth in the specification and/or art and the claimed function(s).
Therefore, defining the structure of the antibody by the function of binding to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80 does not demonstrate possession of the genus because there is no structure-function correlation one could derive from the disclosed function of binding MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
In conclusion, Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of VHH antibodies binding to MHCII, CD11c, DEC205, DC-SIGN, CLEC9a, CD103, CX3CR1, CD1a, or F4/80.
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.
Claims 1, 2, 9, 20, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Stern in US 2012/0276049 A1 published November 1, 2012, cited herewith, and Clay in JP 2019506867 A published on March 14, 2019, as cited herewith from attached English Translation.
Stern teaches a fusion protein comprising a dendritic cell-specific monoclonal antibody and a immunosuppressive / tolerogenic peptide, wherein the DC-specific monoclonal antibody is DEC205, CLEC9A or 33D1 (pg. 1 in ¶ [0009]), pertaining to instant claims 1 and 2. In some embodiments the fusion protein is used for treating multiple sclerosis (MS) and the peptide is myelin basic protein (MBP) or myelin oligodendrocyte protein (MOG) (see pg. 1in ¶’s [0007] and [0008] and pg. c in ¶ [0011]), relating to instant claim 24. Stern teaches that methods of treating autoimmune disease with the fusion protein further comprise administering an addition therapeutic agent including, inter alia, a steroid or non-steroidal anti-inflammatory agent (see pg. 3 in ¶ [0025]). At ¶ [0163] on pg. 17, Stern discloses that the fusion protein is formulated in a compositions further comprising an additional therapeutic agent including anti-inflammatories, steroids, and immunosuppressants (see also claim 4). At ¶ [0100] on pg. 11, Stern teaches that the antigen is linked to the antibody with a linker, and at ¶ [0122] on pg. 12 Stern teaches hydrolysable and non-hydrolysable embodiments of said linker, relating to instant claim 9.
While Stern teaches a composition comprising anti-CLEC9a fused to a self-antigen and an anti-inflammatory agent, Stern does not teach that the antibody is VHH or that the anti-inflammatory is prednisone.
However, Clay teaches an anti-CLEC9a VHH for treating MS (see ¶’s 6 through 8 on pg. 3). On pg. 75 in the first and second full ¶’s, Clay teaches that the anti-Clec9a antibody includes or is used in combination with agents for treating MS including prednisone, methylprednisolone, and dexamethasone, relating to instant claim 20. On pg. 85 in ¶’s four through six, Clay discloses that the anti-Clec9a can be used to inhibit an immune response to an antigen for the treatment of autoimmune disease, which can be achieved by targeting said antigen to antigen presenting cells expressing Clec9a.
A person of ordinary skill in the art would have found it prima facie obvious to use Clay’s anti-CLEC9a VHH and prednisone, methylprednisolone or dexamethasone as the anti-CLEC9a antibody and steroid of Stern’s composition comprising an anti-CLEC9a-antigen fusion protein and immunosuppressive agent. The skilled artisan would have been motivated to combine Stern’s fusion protein + immunosuppressant composition with Clay’s anti-CLEC9a VHH and specific steroids because of the similarity in design, i.e. both teach targeting an autoantigen to a dendritic cell using anti-CLEC9a, and the shared use for treating MS. More particularly, the skilled artisan would have been motivated to use Clay’s anti-CLEC9a VHH as the anti-CLEC9a antibody taught by Stern because Stern does not teach a particular sequence structure, thus the skilled artisan would have turned to the art to develop the anti-CLEC9a embodiment of Stern. This would have led the skilled artisan to consider Clay’s anti-CLEC9a VHH, which the skilled artisan would have recognized as suitable for its intended use based on the fact that it a) binds CLEC9a and b) is taught by Clay as being useful for the same purpose of treating MS that Stern teaches for anti-CLEC9a monoclonal antibodies. “The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)” (see MPEP 2144.07).
Additionally, with respect to combining anti-CLEC9a VHH-antigen fusion protein with prednisone, methylprednisolone, and dexamethasone, the explicit teachings of Clay and Stern teach toward combination of a steroid, as taught by Stern, which includes, e.g. prednisone, as evidenced by Clay. Moreover, “’It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” (see MPEP 2144.06). In the instant case, the anti-CLEC9a-antigen, e.g. MOG antigen, is taught by Stern as useful for treating MS and Clay teaches that prednisone, methylprednisolone, and dexamethasone are also used for treating MS, therefore their combination in a single composition, in view of In re Kerkhoven, would have been prima facie obvious to a person having ordinary skill.
In view of the level of skill evidenced by the references’ teachings and explicit teachings and suggestions, the person of ordinary skill would have had a reasonable expectation of success in use Clay’s anti-CLEC9a VHH and prednisone, methylprednisolone or dexamethasone as the anti-CLEC9a antibody and steroid of Stern’s composition comprising an anti-CLEC9a-antigen fusion protein and immunosuppressive agent. In doing so, one would have arrived at the instant invention of claims 1, 2, 9, 20 and 24.
Claims 1, 2, 6, 9, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Stern in US 2012/0276049 A1 published November 1, 2012, cited herewith and Ploegh in US 2015/0086576 A1 published on March 26, 2015, cited herewith.
Stern teaches a fusion protein comprising a dendritic cell-specific monoclonal antibody and a immunosuppressive / tolerogenic peptide, wherein the DC-specific monoclonal antibody is DEC205, CLEC9A or 33D1 (pg. 1 in ¶ [0009]), pertaining to instant claims 1 and 2. In some embodiments the fusion protein is used for treating multiple sclerosis (MS) and the peptide is myelin basic protein (MBP) or myelin oligodendrocyte protein (MOG) (see pg. 1in ¶’s [0007] and [0008] and pg. c in ¶ [0011]), relating to instant claim 24. Stern teaches that methods of treating autoimmune disease with the fusion protein further comprise administering an addition therapeutic agent including, inter alia, a steroid or non-steroidal anti-inflammatory agent (see pg. 3 in ¶ [0025]). At ¶ [0163] on pg. 17, Stern discloses that the fusion protein is formulated in a composition further comprising an additional therapeutic agent including anti-inflammatories, steroids, and immunosuppressants (see also claim 4). At ¶ [0100] on pg. 11, Stern teaches that the antigen is linked to the antibody with a linker, and at ¶ [0122] on pg. 12 Stern teaches hydrolysable and non-hydrolysable embodiments of said linker, relating to instant claim 9.
While Stern teaches a composition comprising a fusion protein comprising a monoclonal antibody specific for a dendritic cell linked to a self-antigen, e.g. MOG, and an anti-inflammatory / immunosuppressive agent, Stern does not teach that the antibody is VHH specific for MHCII or that the VHH comprises a sortase recognition sequence at the N- or C-terminus.
However, Ploegh teaches that DEC-205 has been proposed as an approach to modulate an immune response, however targeting a peptide to MHCII by attaching a peptide to MHCII-binding VHH using sortase was significantly more effective that targeting the same peptide to DEC-205 using a conventional antibody (see pg. 66 in ¶ [0355]). Ploegh teaches that the MHCII VHH is potentially significantly more effective at inducing tolerance to the antigen than targeting the antigen using DEC-205. Id. Ploegh’s MHCII-antigen construct is created by adding a sortase recognition motif to the N- or C-terminus of a single domain antibody (see Abstract and ¶ [0005] on pg. 1). In ¶ [0373] on pg. 70 through [0375] spanning pg. 70 and 71, Ploegh describes inducing tolerance using an agent comprising an anti-MHCII targeting moiety and a self-antigen for treating autoimmune disease. In ¶ [0393] on pg. 73, Ploegh teaches that the autoimmune disease is, inter alia, multiple sclerosis.
A person of ordinary skill in the art would have found it prima facie obvious to use Ploegh’s anti-MHCII VHH comprising a sortase recognition sequence as the antibody specific to dendritic cells of Stern’s composition comprising a fusion protein and immunosuppressive agent. The skilled artisan would have been motivated to combine Stern’s fusion protein + immunosuppressant composition with Ploegh’s anti-MHCII VHH because of the similarity in design, i.e. both teach targeting an autoantigen to a dendritic cell, and the shared use for treating MS. More particularly, the skilled artisan would have been motivated to use Ploegh’s anti-MHCII VHH over Stern’s exemplary anti-DEC205 monoclonal antibody because Ploegh teaches that MHCII VHH conjugated to an antigen using a sortase-mediated reaction significantly more effective at targeting the antigen to a dendritic cell than a conventional anti-DEC205 antibody conjugated to the same antigen. “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983).” (see MPEP 2144 II.). In the instant case, the person having ordinary skill in the art would have recognized from Ploegh’s explicit disclosure and experimental evidence that sortase-conjugated MHCII VHH-antigen design is advantageous over Stern’s preferred embodiment, therefore the skilled artisan would have been motivated to use said sortase-conjugated MHCII VHH-antigen design to target a self-peptide to a dendritic cell as taught by both Stern and Ploegh.
Additionally, with respect to combining anti-MHCII VHH-antigen fusion protein with an anti-inflammatory, the explicit teachings Stern teach toward combination of a steroid. Moreover, “’It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” (see MPEP 2144.06). In the instant case, the skilled artisan would recognize that the anti-MHCII VHH-antigen fusion protein of Stern in view of Ploegh as useful for treating MS and steroids are also known for treating MS, therefore their combination in a single composition, in view of In re Kerkhoven, would have been prima facie obvious to a person having ordinary skill.
In view of the level of skill evidenced by the references’ teachings and explicit teachings and suggestions, the person of ordinary skill would have had a reasonable expectation of success in use Ploegh’s anti-MHCII VHH comprising a sortase recognition sequence as the antibody specific to dendritic cells of Stern’s composition comprising a fusion protein and immunosuppressive agent. In doing so, one would have arrived at the instant invention of claims 1, 2, 6, 9, and 24.
Claims 1, 2, 6, 9-10, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Sterling et al. 2018. ACS Nano. 12:6637-6647, cited herewith, in view of Ploegh in US 2015/0086576 A1 published on March 26, 2015, cited herewith.
Sterling teaches using anti-CD11c to target immunosuppressive payloads comprising an antigen and rapamycin to dendritic cells for the purpose of generating regulatory T cells (see abstract, and the last ¶ on pg. 6640 of the first col. spanning the second col., and Figure 3). Sterling teaches that such targeted payloads would be useful for inducing immune tolerance in the context of allogenic transplant (see pgs. 66317-6638). On pg. 6644, in the first full ¶ of the first col., Sterling teaches “CD11c-[payload] promoted DC-specific targeting to a greater extent than DC-SIGN-[payload].”
While Sterling teaches targeting an antigen and anti-inflammatory / immunosuppressive payload to a dendritic cell via an anti-CD11c, Sterling does not teach that the anti-CD11c is VHH or that the antigen is conjugated to the antibody.
However, Ploegh teaches that VHH antibodies are advantageous for therapeutics. “Unlike other mammalian species, camelids possess an additional class of antibodies whose binding site is constructed from a VH domain only. These domains can be expressed in bacteria as so-called nanobodies. Their small size and ease of manipulation make them attractive targets for the construction of therapeutics.” (see, e.g., ¶ [0409] in Example 3). Ploegh broadly describes targeting an antigen to an immune cell, e.g. dendritic cell (see ¶ [0235] on pg. 38). VHH’s are the exemplary embodiment of antibodies that Ploegh uses to attach antigens via sortase-mediated click chemistry (see, e.g., ¶ [0014] on pg. 2 and Examples 5 and 6). More particularly, Ploegh’s exemplary MHCII-antigen construct is created by adding a sortase recognition motif to the N- or C-terminus of a single domain antibody (see Abstract and ¶ [0005] on pg. 1), pertaining to instant claim 6. In ¶ [0373] on pg. 70 through [0375] spanning pg. 70 and 71, Ploegh describes inducing tolerance using an agent comprising an anti-MHCII targeting moiety and a self-antigen. Particularly, Ploegh teaches that tolerogenic dendritic cells can be generated that either delete autoreactive T cells or induce regulatory T cells. Id. Regarding instant claim 9, Ploegh discusses linkers used to conjugate VHH to an moieties known in the art including hydrolysable and non-hydrolysable embodiments (see, e.g. ¶ [0319] on pg. 58).
Consider that “’[a] person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.’ Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account ‘the inferences and creative steps that a person of ordinary skill in the art would employ.’ Id. at 418, 82 USPQ2d at 1396.” (see MPEP 2141 II.C.).
In the instant case, a person having ordinary skill in the art would have found it prima facie obvious to combine the teachings of Sterling and Ploegh in view of the ordinary level of skill because both Sterling and Ploegh teach targeting antigens to dendritic cells for inducing tolerance and the generation of regulatory T cells. The person of ordinary skill, reading Sterling would have inferred an advantage of targeting CD11c over other potential dendritic targets, because Sterling teaches that targeting CD11c was dendritic cell-specific “to a greater extent.” Moreover, the advantage of using VHH over conventional antibodies would have been apparent to POSITA from the teachings of Ploegh. In choosing between Sterling’s nanoparticle and Ploegh’s sortase-mediate click chemistry designs, in view of Ploegh’s disclosed advantages of VHH, i.e. small size and ease of manipulation, the skilled artisan would have chosen Ploegh’s sortase-mediate click chemistry design, which the skilled artisan would have inferred as retaining the VHH’s advantage of having a small size. The expectation of some advantage is the strongest rationale, see citation of MPEP 2144 II supra.
Regarding, combining the anti-CD11c VHH conjugated to antigen with an immunosuppressive in the same composition, consider that the purpose of inducing tolerance as taught by both Sterling and Ploegh would have been apparent as relevant to transplant patients, as explicitly taught by Sterling and/or autoimmune disease as taught by Ploegh. Such patients are routine treated with immunosuppressants, as evidenced by Sterling’s discussion on the use of rapamycin. It would have been prima facie obvious to the skilled artisan to combine two composition known in the art for the same purpose of promoting tolerance / suppressing the immune response in a single composition. See citation of MPEP 2144.06 supra. Additionally, Sterling evidences that dendritic cell targeting of immunosuppressants, such as rapamycin, have a greater ability to induce Tregs over non-targeted administration (see Fig. 3 on pg. 6640). Thus, the claimed embodiment of targeting an anti-inflammatory by conjugation to a VHH would also have been prima facie obvious in view of the art and the inferences / creative steps a skilled artisan would have taken.
In view of the level of skill evidenced by the references’ teachings and explicit teachings and suggestions, the person of ordinary skill would have had a reasonable expectation of success in combining the teachings of Sterling and Ploegh. In doing so, one would have arrived at the instant invention of claims 1, 2, 6, 9-10, and 24.
Conclusion
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/B.K.S./Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644