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 .
Claims 51-70 are pending and under consideration.
Information Disclosure Statement
The IDS filed 02/08/2024 was considered but several citations were lined through. In some cases, the information in the citation(s) were cut off (e.g., reference 114), or no publisher information was provided (e.g., references 115-116). Further, it is noted that reference number 84 (Kreiter et al.) indicated that pages 692-696 were submitted however only a one page “erratum” was submitted and considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See page 44, lines 30+.
The specification is further objected to on page 107. Lines 7 and 18 appear to disclose an amino acid sequence without its respective sequence identifier (SEQ ID NO). See 37 CFR 1.821(c). 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825.
The specification is further objected to on page 108, lines 22-24. This appears to be a footnote identifying a reference (Sugimoto et al.). But it’s unclear what the footnote is in reference to as the preceding paragraph does not provide a nexus to the reference.
Claim Objections
Claim 61 is objected to for reciting “MHCII” twice as part of the Markush grouping.
Claim 51 is objected to for reciting “a first targeting unit, a first joint region;” as it’s unclear why the “first joint region” is not separated like part “c” that comprises “a second joint region”. While it is assumed there is no structural difference in that the first joint region immediately follows the first targeting unit, it would be more clear, for consistency, for the first joint region to be separated.
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 51-56, 58-59, 61-62, 65-67, and 70 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.
Regarding claims 51-56, 58, 61, 65-67 and 70; the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 52-54, 56, 59, 62 the phrase "for example" or “e.g.” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 61 is further indefinite for reciting “selected from the group consisting of TGFβ receptor (TGFβR1, TGFβR2, or TGFβR3)” as it’s unclear if the receptors in the parenthesis are exemplary or if they are part of the claimed invention.
Claim 65 is rejected for being vague and unclear for reciting “as defined in Claim 51”. As written, it’s not clear if, “A multimeric protein, such as a dimeric protein, as defined in claim 51,” is truly a dependent claim or if it’s only referring to some aspect of the dimeric protein. For examination purposes, Claim 65 will be interpreted as wholly dependent from Claim 51.
Claim Rejections - 35 USC § 112
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 51-70 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. This is a Written Description rejection.
The claims are broadly drawn to a “tolerance-inducing” construct comprising:
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The specification teaches [0169] that a “tolerance-inducing construct” is one that does not elicit an inflammatory immune response but rather induces tolerance towards the T cell epitopes comprised in the antigenic unit when administered to a subject in a form suitable for administration and in an amount effective to induce tolerance. The constructs generally have the structures set forth in Figures 1-3 where the first and a second targeting unit targets antigen-presenting cells (APCs):
The term “targeting unit” is referred to [0300] as a unit that delivers the construct of the disclosure to an antigen-presenting cell and interacts with surface molecules on the APC, e.g. binds to surface receptors on the APC, without inducing maturation of the cell. The APC internalizes the construct and presents the T cell epitopes comprised in the antigenic unit on MHC on its surface in an anti-inflammatory, tolerogenic manner. In some embodiments, the targeting unit comprises or consists of a moiety that binds to a surface molecule on APC which can include such diverse proteins as TGFβ receptors, interleukin receptors, GM-CSFR, FLT3, CCR7, CD11b, CD11c, CD103, CD14, CD36, CD205, CD109, VISTA, MARCO, MHCII, CD83, SIGLEC, MGL/Clec10A, ASGR (ASGR1/ASGR2), CD80, CD86, Clec9A, Clec12A, Clec12B, DCIR2, Langerin, MR, DC-Sign, Treml4, Dectin-1, PDL1, PDL2, HVEM, CD163, and CD141. Further, these targeting constructs [0302] can be the natural ligand to the receptors, a synthetic ligand, or an scFV or an antibody or binding fragments thereof. Thus, the claims are drawn to very broad genus of antigens or ligands that can target a genus of receptors or protein molecules on all antigen-presenting cells.
Further, regarding the “antigenic” unit, the specification teaches [0325] that the antigenic unit of the tolerance-inducing construct of the disclosure comprises one or more T cell epitopes of a self-antigen, including, but not limited to, a T reg epitope or inhibitory neoantigen, an allergen, an alloantigen or a xenoantigen. The T cell epitope comprised in the antigenic unit of the construct of the disclosure [0349] can range in length from 7 to about 200 amino acids, with the longer T cell epitopes possibly including hotspots of minimal epitopes, and the “number” of T cell epitopes in the antigenic unit may vary, and depends on the length and number of other elements included in the antigenic unit [0353]. For example, in some embodiments, the antigenic unit comprises 1 to 10 T cell epitopes such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 or 10 T cell epitopes or 11 to 20 T cell epitopes, such as 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 T cell epitopes or 21 to 30 T cell epitopes. And, in some embodiments, the T cell epitopes are randomly arranged in the antigenic unit [0357]. Thus, the “antigenic” unit is drawn to a massive genus of extremely diverse amino acid sequences regarded as “epitopes” derived from any and all allergens, alloantigens, xenoantigens, self-antigens. These epitopes can also be derived from amino acids of the targeting units forming multiple polypeptide complexes.
The claims are further broadly drawn to “treating conditions” involving undesired immune reactions such as any and all autoimmune disorders, allergic disease, and graft rejections comprising administering pharmaceutical compositions of the claimed tolerance-inducing constructs.
However, what applicants have demonstrated possession of are several species of amino acid constructs that appear to have some properties of eliciting the presentation of regulatory T cells and IL-10. For example, when mice were vaccinated with these constructs, splenocytes were harvested and IL-10 was detected with only low background levels of IFN-γ detected (See figures 13A-C ). In another example, some constructs showed the detection of Foxp3+ cells, indicating the presence of regulatory T cells or Tregs (Figure 14). The various species of constructs are described on pages 117- 122 wherein, in much of the case, amino acids derived from myelin oligodendrocyte glycoprotein (MOG) has been incorporated as one species of antigenic domain into the construct. See for example SEQ ID Nos: 23-34. In other instances, many of the examples include certain amino acids from IL-10 as targeting moieties such as SEQ ID Nos: 23-25, and 29-32. Other similar targeting moieties include amino acids derived from CCL3L1 and anti-DEC205 scFVs.
Thus, the claims broadly encompass a huge genus of structurally diverse complexes as set forth above while only a few representative species have been adequately described. A description of a genus of may be achieved by means of a recitation of a representative number of species, defined by structure, falling within the scope of the genus. However, the instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus. The species described do not represent the genus of any and all APC targeting domains, and any and all antigenic units that would predictably induce tolerance or induce tolerance to treat a subject having an undesired immune reaction. The disclosure fails to describe the common attributes or characteristics that identify members of the genus. For example, the species of polypeptides disclosed that showed IL-10 detection or presence of regulatory T cells is insufficient to describe the large genus. The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, inventor was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991). An applicant shows that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of “tolerance-inducing” constructs to describe and enable the genus as broadly claimed.
Regarding the treatment of undesired immune reactions, Jeffrey Bluestone (“Mechanisms of tolerance”; Immunological Reviews, Vol. 241, Issue 1, Aril 2011) teaches (page 14, 1st column) that current immunosuppressive treatments are usually efficient at preventing acute rejection of solid allografts. However, little progress has been made over the last two decades in avoiding chronic rejection, and current therapies induce general immunosuppression that can affect the ability of recipients to fight tumors and infections. Further, regarding regulatory T cells, Bluestone teaches that the notion that immune responses could be controlled by specialized suppressor T cells was only revived within the past 15 years (page 8, 1st column). These studies led to the identification of CD4+CD25+Foxp3+ Tregs and their crucial role in peripheral tolerance. However, the mere detection of T-regs in vitro does not predictably translate into treating in vivo autoimmune disorders or predicting that a construct may be labeled as “tolerant inducing”. For example, de Wolf et al. (PLoS One, 12(6) June 2017) teaches (abstract) that in exploratory clinical trials, healthy adults were vaccinated with an influenza subunit vaccine plus or minus the adjuvant MF59®, an adjuvanted hepatitis B subunit vaccine or a live attenuated yellow fever vaccine. Frequencies and phenotypes of resting (rTreg) and activated (aTreg) subpopulations of circulating CD4+ Treg were determined and compared to placebo immunization wherein vaccination with influenza vaccines did not result in significant changes in Treg frequencies and phenotypes (abstract). In contrast to vaccination, infection with an influenza virus was shown to increase Treg frequencies or absolute numbers in human peripheral blood and influenza A virus infection of mice induced a viral-specific Treg response locally as well as systemically that preceded the Teff response (page 10). In contrast to the data in the specification, the reference further teaches that phenotypic characterization of Treg after vaccination is a first step to analyze the effect of vaccination on Treg.
In the absence of sufficient guidance, direction, and disclosure of the claimed engineered tolerance-inducing constructs, the specification as filed does not provide sufficient written description for the genus as broadly claimed. For inventions in an unpredictable art, adequate written description of a genus, which embraces widely variant species cannot be achieved by disclosing only one (or none) species within the genus. 12. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed structure of the encompassed genus of tolerance-inducing constructs, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiefs v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v.Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The closest prior art appears to be related to vaccines against HPV. (Brekke et al. WO2013092875, June 2013, applicant’s IDS). Brekke et al. teach vaccibody HPV E7 construct VB1005 homodimeric protein (comprising a native leader sequence from a human LD78-beta, a full length LD78-beta sequence, a human hinge-region 1 from IgG3, a human hinge region 4 from IgG3, a Gly-Ser linker, a human CH3 domain from IgG3, a Gly-Leu linker, a wild-type human papilloma virus oncoprotein E7 separated by a Gly-Ser linker) which is used in preparing a pharmaceutical composition for treating or preventing a HPV induced disease or condition. This sequence was 87.3% identical to SEQ ID NO:34 disclosed on page 120 of the specification. However, this particular construct is not tolerant-inducing.
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No claim is currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643
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