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 .
The response, substitute specification and amendment to the claims filed 2-18-2026 has been entered.
Status of Claims
Claims 1-28 and 30 are pending. Claim 29 has been canceled.
Sequence Requirements
Applicant’s response filed 2-18-2026 has resolved the outstanding sequence requirements.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The foreign priority document is not in English, and a Certified translation has not been provided. As such, the effective filing date for prior art purposes is the international filing date of 10/20/2021.
Election/Restrictions
Applicant's election with traverse of Group I and species of bacteria as Bacillus for flagellin component in the reply filed on 2-18-2026 is acknowledged. The traversal is on the ground(s) that the Office has not shown there would be a serious burden on the examiner if restriction is not provided. This is not found persuasive because this application was filed under 35 USC 371 and the Unity of Invention standard is applied. The Unity of Invention has demonstrated that the Groups of inventions and species are not linked by a “special technical feature” which defines over the art as set forth in the Lack of Unity requirement in the Office Action mailed 11-18-2025.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-19 and 23-28 are under examination. Claims 20-22 and 30 are withdrawn from consideration.
Information Disclosure Statement
The information disclosure statements have been considered. Initialed copies are enclosed.
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 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(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 1-18 and 23-28 are rejected under 35 U.S.C. 112(a), 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
MPEP § 2163 states 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, 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. 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.
Scope of the claimed genus
Claim 1 is drawn to a fusion protein comprising a flagellin, a fragment thereof or a variant thereof and an IGg4 variant Fc region that prevents Fab arm exchanges. Claims 2 and 3 are drawn to wherein the flagellin is derived from a genus of bacteria. Claim 4 is drawn to wherein the flagellin comprises a conserved sequence recognized by TLR5. Claim 5 provides for fargments that have a hypervariable region removed from wild-type flagellin. Claim 14 claims the flagellin, fragment or variant thereof consists of an amino acid sequence selected from SEQ ID NO: 1-5 or an amino acid sequence exhibiting at least 80% sequence homology thereto. Claim 15 is drawn to SEQ ID NO: 6 or 7 or an amino acid sequence exhibiting at least 80% sequence homology thereto. Claims 16 is drawn to the linker. Claim 18 is drawn to nucleic acid encoding the fusion protein of claim 1. Claim 21 is drawn to a composition or a vaccine adjuvant comprising the fusion protein of claim 1 as an active ingredient. The USPTO provides claim terms with broadest reasonable interpretation in light of the specification.
The instant specification defines “active fragment” at pages 7-9 of the specification the flagellin may include full-length flagellin, or an active fragment thereof. In addition, terms such as “flagellin”, “flagellin N-terminal constant region” and “flagellin C-terminal constant region” include naturally occurring amino acid sequences, or it may also comprise an amino acid sequence substantially identical to or similar to the amino acid sequence of a naturally occurring flagellin, flagellin N-terminal constant region, or flagellin C-terminal constant region, respectively. An “active fragment” of flagellin, flagellin N-terminal constant region, flagellin C-terminal constant region, or any other portion of flagellin comprises at least about 50, 75, 100, 125, 150, 200, 250 or at least 300 contiguous amino acids and/or less than about 300, 250, 200, 150, 125, 100 or 75 amino acids of contiguous amino acids, and combinations of these may also be included as long as the lower limit is less than the upper limit. The active fragment may refer to a fragment capable of activating the TLR5 pathway in a host. The active fragment is capable of activating the TLR5 pathway with at least about 50%, 75%, 80%, 85%, 90%, or 95% of full-length flagellin, or activates the TLR5 pathway to the same or essentially the same extent as the full-length flagellin or flagellin region, or activates the TLR5 pathway to a higher degree compared to full-length flagellin or flagellin region. The present invention, the active fragment may refer to at least one portion of flagellin exhibiting TLR5 pathway activity. The “at least one portion” may refer to a portion exhibiting TLR5 pathway activity in domains 0, 1, 2 and 3 of flagellin. More specifically, the active fragment may be a hypervariable region removed from full-length flagellin. The hypervariable region may vary depending on the type of bacteria from which flagellin is derived, and among the entire sequence of a specific flagellin, the sequence corresponding to the hypervariable region can be easily identified and removed by those skilled in the art. For example, N- terminal domains 0, 1, 2; domain 3; and domain 3, or domains 2 and 3 may be hypervariable regions in the case of full-length flagellin comprising C- terminal domains 2, 1, 0, and N-terminal domain 0, 1; domain 2; domain 2 may be a hypervariable region in the case of full-length flagellin including C-terminal domains 1 and 0. Alternatively, in the case of flagellin of a form not including a hypervariable region (For example, flagellin derived from many Gram-positive bacteria may not contain a hypervariable region.), the sequence of a hinge region in which folding of the flagellin protein occurs may be partially removed. It should be noted that the claims recite “fragment” not “active fragment”. The broadest reasonable interpretation of the “fragment” includes fragment less than 300, 250 and 75 contiguous amino acids. The active fragment may refer to at least one portion of flagellin exhibiting TLR5 pathway activity. The instant specification does not limit the fragment to a particular portion of flagellin or a size.
The instant specification defines “variant” in at pages 9-11 as including proteins having the full-length sequence of wild-type flagellin as well as amino acid sequence variants thereof. In the present invention, the variant refers to a protein having a different sequence due to deletion, insertion, non-conservative or conservative substitutions, substitution of amino acid analogs or a combination thereof of some amino acid residues of a wild-type flagellin or a fragment thereof. Amino acid exchanges that do not entirely alter the activity of the molecule (ie, the ability to activate the TLR5 pathway) are known in the art (H. Neurath, R. L. Hill, The Proteins, Academic Press, New York, 1979). At page 10, the variant of the present invention may be a full-length flagellin modified by phosphorylation, sulfation, acrylation, glycosylation, methylation, farnesylation or the like or a fragment thereof. The variant of flagellin or fragment thereof is capable of activating the TLR5 pathway by at least about 50%, 75%, 80%, 85%, 90%, or 95% of full length flagellin or fragment thereof, or activating the TLR5 pathway to the same or essentially the same extent as full-length flagellin or a fragment thereof, or higher activation of the TLR5 pathway compared to full-length flagellin or a fragment thereof is set forth at page 10. The broadest reasonable interpretation of “variant” includes proteins having a different sequence due to deletion, insertion, non-conservative or conservative substitution or combinations thereof of some amino acid residues of a WT flagellin or fragment. The variant is not limited in number of changes or size and includes variants of a fragment.
The instant specification defines “percent sequence homology” in paragraph briding pages 10-11: the term “percent (%) sequence homology” is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residue in the reference polypeptide, after aligning the sequences and introducing gaps, without considering any conservative substitutions as part of the sequence identity to achieve the maximum percent sequence identity if necessary. Alignment for purposes of determining percent amino acid homology can be achieved, for example, using publicly available computer software programs and various methods that are within the skill in the art and using BLAST, blast-2, ALIGN, or Megalign (DNASTAR) software. The term “homology” is interpreted as sequence identity due to the definition above.
The specification provides for a human IgG4 Fc variant that has a mutation that prevents Fab arm exchange. This language provides for unlimited mutation of the Fc variant The specification contemplates any mutation that can prevent Fab arm exchange and can include a loss, insertion or substation of an amino acid that occurs in one or more of the hinge, CH2 and CH3 of the Fc. Preferably the mutation confers inter-chain disulfide bond formation (pages 11-13). Limited selected mutations are known to the art and the language is intended to encompass unlimited variants sequence including deletion, insertion, non-conservative or conserverative substitutions of one or more amino acid residues (paragraph bridging pages 13-14).
Assessment of whether species are support in the original specification
The specification discloses Fc-hIgG4-Bs flagellin and specific hIgG4 mutations set forth in claim 19 represented by SEQ ID NOS: 49, 51, 53, 55, 57, 59, 61 and 63. The examples had the activity of binding to TLR5 (see Figs. 2-4).
In addition, the complete structure of the following species was disclosed:
SEQ ID NO: 1-5 are the amino acid sequence of full length flagellin from Bacillus subtilis, Salmonella Dublin, Pseudomonas aeruginosa, Shigella flexneri and Escherichia coli respectively.
SEQ ID NO: 6-11 are the amino acid sequences of human IgG4 Fc S228P mutant, human IgG4 Fc S228P + S220P (PGK), hIgG4 Fc S228P mutant + G223T (PGK), IgG4 Fc S228P mutant + P224H, hIgG4 Fc S228P mutant + P225T, and hIgG4 Fc S228P mutant – LGK respectively.
SEQ ID NO: 12 is a linker sequence.
SEQ ID NO: 92 is a hinge sequence.
SEQ ID NO: 49, 51, 53, 55, 57, 59, 61 and 63 are amino acid sequences of the fusion proteins (full length Bacillus flagellin and with hIgG4 Fc and the presence or absence of CPSC or CPPC combined with limited individual mutations in the Fc region). The CPSC and CPPC are mutations that are described to provide for the function of prevention of Fab arm exchange.
There was no disclosure of other fusion proteins comprising fragments or variants of flagellin or hIgG4 that were able to bind TLR5 where the Fc variant had a mutation that prevents Fab arm exchange. There was no disclosure of other fusion proteins that were vaccine adjuvants. Please note an adjuvant is an ingredient used in vaccine to create a stronger immune response.
There was no disclosure of sequences with 80% sequence identity to SEQ ID NO: 1-5 or fragments or variants that had the claimed ability of being recognized by TLR5 and functioning as a vaccine adjuvant having an Fc variant region that has a mutation that prevents Fab arm exchange.
In summary, for these reasons, the skilled artisan would reasonably conclude that the inventor(s), at the time the application was filed, had possession of the fusion proteins of claim 19 at the time the invention was filed.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that 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.
In the instant case, the disclosure of SEQ ID NOs: 49, 51, 53, 55, 57, 59, 61 and 63 are not representative of the genus of fragments and variants thereof of both flagellin and of hIgG4 Fc variants which have mutations that prevent Fab arm exchange. The disclosure of the sequences are not representative of the entire genus encompassed by fragments and variants of flagellin of hIgG4 Fc variants since they are not limited to a particular portion of flagellin or size and the variants can comprise any number of alterations and the Fc variants are without limitation. SEQ ID NO: 49, 51, 53, 55, 57, 59, 61 and 63 are also not representative of a sequence exhibiting at least 80% sequence homology thereto.
With the aid of a computer, one of ordinary skill in the art could identify all of the peptides with at least 80% homology to SEQ ID NOs: 1-5. However, there is no teaching regarding which 20% of the amino acids can vary from SEQ ID NO: 1-5 and still have the claimed function. Importantly, claims 14 and 15 claim an amino acid sequence exhibiting at least 80% sequence homology to the claimed sequences or fragments or variants thereof. One of ordinary skill in the art would not know which residues could vary from the fragment or variants since the fragments and variants are not described in the specification or the claims.
Identifying characteristics and structure/function correlation
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe the structural, physical and/or chemical properties of the flagellin fragments and variants that leads to the claimed functions.
The data do not suggest the physical basis for the claimed activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. Understanding the physical basis for the claimed activity is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
This is an issue of written description. The specification does not make clear which proteins are in the genus and which are not because it does not describe the physical basis for the claimed activity. In other words, the specification does not describe which proteins to make.
In conclusion, for the reasons presented above, the skilled artisan would reasonably conclude that the inventors, at the time the application was filed had full possession of the fragments and variants. Therefore, only SEQ ID NO: 49, 51, 53, 55, 57, 59, 61 and 63 satisfy the written description requirements of 35 U.S.C. 112, first paragraph.
Claims 12, 11, 16 and 17 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
As to claim 12, the claim is indefinite as reference “The fusion protein” but does not have antecedent basis for this term. It is believed that Applicant has not provided a proper claim dependency here. The claim has been examined as depending on claim 1.
Claims 11, 16 and 17 are indefinite in that Markush claims must use closed language “selected from the group consisting of: A, B and C”. Since the group is not closed in each of these claims, it is unclear which embodiments are included or excluded in the recited group. Clarification is requested.
Claims 25-27 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 25-27 merely recite the intended use of the pharmaceutical composition of claim 23 and therefore do not properly further limit the structure of the composition per se. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 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.
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.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1-17, 19 and 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al WO 2020/218829, published 10-29-2020 with priority to 4-22-2019. All references are made with respect to the English language equivalent US 2022/0194993 by Cho et al) in view of KR20190095946 (cited on IDS, google translation provided herein).
Cho et al teaches Fc-hIgG4-Bsflagellin (SEQ ID NO:10) having the identical Bs flagellin sequence (see Figure 4 and SEQ ID NO:10). Cho et al also teach he fusion protein according to wherein the fragment has a hypervariable region removed from wild-type flagellin. The fusion protein wherein the flagellin fragment comprises at least one selected from the group consisting of C-terminal domain 0, C-terminal domain 1, C-terminal domain 2, N-terminal domain 2, N-terminal domain 1, N-terminal domain 0 of wild type flagellin and a domain exhibiting at least 80% amino acid sequence homology with each of the domains. Cho et al teaches wherein the Bacillus subtilis flagellin variant shows at least 80% amino acid sequence homology with wild-type flagellin and exhibits Toll-like receptor 5 (TLR5) stimulating activity. Cho et al teaches that the immunoglobulin Fc region is derived from an Fc of human or animal immunoglobulin IgG, IgM, IgD, IgA or IgE and wherein the immunoglobulin Fc region is derived from an Fc of human or animal immunoglobulin IgG1, IgG2, IgG3 or IgG4. Additionally, Cho et al teach that the immunoglobulin Fc region comprises at least one selected from the group consisting of CH1, CH2, CH3 and CH4 domains and wherein the immunoglobulin Fc region further comprises a hinge region. The N-terminus or C-terminus of the flagellin, the fragment thereof or the variant thereof is bound to the N-terminus or C-terminus of the immunoglobulin Fc region. The flagellin, the fragment thereof, or the variant thereof; and the immunoglobulin Fc region is linked via a linker (see Figure 1). Cho et al also teach a composition or a vaccine adjuvant comprising the fusion protein of claim 1 as an active ingredient. (see claims) Cho et al differs by not teaching that the hIgG4 Fc is a variant that has a mutation that prevents Fab arm exchange.
KR20190095946 teach mutations of the hIgG4 Fc region and hinge that provide for reduced Fab arm exchange, to provide for better bioprocessing properties and preventing reduction in therapeutic activity because of Fab arm exchange. KR20190095946 teaches that arm exchanges were attributed to IgG4 core-hinge sequence with determinants in the CH3 domain (see Description). KR20190095946 teaches various mutations (serine 228), residues at various positions including 196, 217, 220, 224 or 225 selected from K196P, S217P, G220T, P224H or P225T (see Summary of the Invention paragraph 3) including a CPSC -> CPPC hinge region mutant that provides stability and avoids Fab-arm exchange without any therapeutic risk (see Introduction section).
It would be prima facie obvious to a person of ordinary skill in the art to create a flagellin and hIgG4 Fc variant fusion protein with mutations that prevent Fab arm exchange by substitution hIgG4 Fc of Cho et al with the hIgG4 variant Fc of KR20190095946 to create a flagellin fusion with a hinge comprising CPPC as claimed because a person of ordinary skill in the art would look to would look to the teachings of KR20190095946 teach mutations of the hIgG4 Fc region and hinge that provide for reduced Fab arm exchange, to provide for better bioprocessing properties and preventing reduction in therapeutic activity as a result of Fab arm exchange. There is a reasonable expectation of success given that hIgG4 Fc-fusion proteins inherently safe as non-live, protein subunit therapeutic in the art as evidenced by Cho et al. With respect to claims 2 and 3, the limitation “derived from” is interpreted as a product by process limitation. MPEP 2113 states "The patentability of a product does not depend on its method of production. If the product in the product-by-process limitation is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” Therefore, determination of patentability is based on the product itself. In the instant case, Cho et al teaches the flagellin is from Bacillus subtilis ( identical to SEQ ID NO:1 herein), meeting the limitations of the claims. With respect to claim 4, Fc-hIgG4-Bsflagellin Cho et al teaches the fusion protein has TLR5 stimulating activity significantly improved over other IgG4 Fc fusions (see Figure 4). hIgG4 Fc of Cho et al with hIgG4 Fc variant of which has a mutation that prevents Fab arm exchange is prima facie obvious in view of the known benefits of reducing Fab arm exchange and the in vivo compatibility of such. The fusion would be expected to reduce polymerization and therefore provide for increase stimulation of TLR5 as claimed. As to claims 25-27, these claims recite mere intended use of a composition which is not given patentable weight in a product as they do not structurally further limit the composition.
Claims 1-4, 6-15, and 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over KR20080074556 (cited on IDS, google translation provided herein) in view of KR20190095946 (cited on IDS, google translation provided herein).
KR20080074556 teaches PAS-flagellin fusion protein in which the PAS factor is fused to the N-terminus of the flagellin protein. KR20080074556 teaches the PAS-flagellin fusion protein has TLR5 stimulating activity significantly improved (bottom of p. 2) as it prevents flagellin polymerization. KR20080074556 teaches a vaccine adjuvant with PAS-flagellin fusion protein as an active ingredient (middle of p. 2). With respect to claims 2 and 3, the limitation “derived from” is interpreted as a product by process limitation. MPEP 2113 states "The patentability of a product does not depend on its method of production. If the product in the product-by-process limitation is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” Therefore, determination of patentability is based on the product itself. In the instant case, KR20080074556 teaches the flagellin is from Vibrio Vulnificus, meeting the limitations of claims 2 and 3 and unlimited variation or fragments of Bacillus subtilis. KR20080074556 teaches the PAS-flagellin fusion protein has TLR5 stimulating activity significantly improved (bottom of p. 2). KR20080074556 teaches PAS-flagellin fusion protein in which the PAS factor is fused to the N-terminus of the flagellin protein (bottom of p.2). KR20080074556 does not teach a fusion protein of an immunoglobulin hIgG4 Fc region with flagellin or where the Fc fusion is an hIgG4 Fc variant that has a mutation that prevents Fab arm exchange However, the teachings of K KR20190095946 cure this deficiency.
KR20190095946 teach mutations of the hIgG4 Fc region and hinge that provide for reduced Fab arm exchange, to provide for better bioprocessing properties and preventing reduction in therapeutic activity as a result of Fab arm exchange. KR20190095946 teaches that arm exchanges was attributed to IgG4 core-hinge sequence with determinants in the CH3 domain (see Description). KR20190095946 teaches various mutations (serine 228), residues at various positions including 196, 217, 220, 224 or 225 selected from K196P, S217P, G220T, P224H or P225T (see Summary of the Invention paragraph 3) including a CPSC -> CPPC hinge region mutant that provides stability and avoids Fab-arm exchange without any therapeutic risk (see Introduction section).
It would be prima facie obvious to a person of ordinary skill in the art to create a flagellin and hIgG4 Fc variant fusion protein with mutations that prevent Fab arm exchange by substitution PAS with the hIgG4 variant Fc to create a flagellin fusion with a hinge comprising CPPC as claimed because a person of ordinary skill in the art would look to the teachings if KR20080074556 which provide for a fusion partner that would both prevent polymerization of flagellin and provide for a vaccine adjuvant comprising a flagellin fusion protein as an the active ingredient. Therefore, a person of ordinary skill in the art would look to the teachings of KR20080074556 and have a reason to create an Fc-flagellin fusion protein as a vaccine adjuvant due to the stabilizing nature of the hIgG4 Fc variant, safety profile and as a means to reduce flagellin polymerization and therefore preserve the TLR5 stimulating activity. There is a reasonable expectation of success given that hIgG4 Fc-fusion proteins inherently safe as non-live, protein subunit therapeutic in the art, and the PAS fusion was shown to have reduced flagellin polymerization and maintained stimulating activity. With respect to claims 2 and 3, the limitation “derived from” is interpreted as a product by process limitation. MPEP 2113 states "The patentability of a product does not depend on its method of production. If the product in the product-by-process limitation is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” Therefore, determination of patentability is based on the product itself. In the instant case, KR20080074556 teaches the flagellin is from Vibrio Vulnificus, meeting the limitations of claims 2 and 3. With respect to claim 4, KR20080074556 teaches the PAS-flagellin fusion protein has TLR5 stimulating activity significantly improved (bottom of p. 2). With respect to claim 12, KR20080074556 teaches PAS-flagellin fusion protein in which the PAS factor is fused to the N-terminus of the flagellin protein (bottom of p.2). The substitution of PAS with hIgG4 Fc variant which has a mutation that prevents Fab arm exchange is prima facie obvious in view of the known benefits of reducing Fab arm exchange and the in vivo compatibility of such. The fusion would be expected to reduce polymerization and therefore provide for increase stimulation of TLR5 as claimed. As to claims 25-27, these claims recite mere intended use of a composition which is not given patentable weight in a product as they do not structurally further limit the composition.
Claims 1-4, 6-16, and 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over KR20080074556 (cited on IDS, English copy provided herein) in view of in view of KR20190095946 (cited on IDS, google translation provided herein) and further in view of GenBank sequence ADM39502.1 January 30, 2014 to Zeigler.
The teachings of KR20080074556 and KR20190095946 are presented above in detail. The references as combined do not teach the sequence of the flagellin meets the limitation of claim 16. However, the teachings of GenBank sequence ADM39502.1 January 30, 2014 to Zeigler cure this deficiency.
ADM39502.1 to Zeigler is a Bacillus subtilis subspecies spizizenii flagellin sequence having 100% identity as compared to SEQ ID NO:1.
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It would be obvious to a person of ordinary skill in the art to substitute any available flagellin for the flagellin used in the hIgG4 Fc variant-flagellin fusion protein as combined supra because flagellins as a genus have known TLR5 inducing activity. There is a reasonable expectation of success given that the proteins are both flagellin.
Claims 1-4, 6-8, 11, 13, 15, 17 and 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over KR20080074556 (cited on IDS, English copy provided herein) in view of KR20190095946 (cited on IDS, google translation provided herein) and further in view of WO2014190356.
The teachings of KR20080074556 and KR20190095946 are presented in detail above.
The references as combined do not teach the sequence of hIgG4 Fc variant region having SEQ ID NO:6.
WO2014190356 teaches fusion proteins comprising an hIgG4 Fc variant where there is a S228P mutation that provides for preventing Fab arm exchange (see SEQ ID NO:20 aligned with instant SEQ ID NO:6 below)
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It would have been obvious to a person of ordinary skill in the art to optimize the Fc region sequence. A person would look to the teachings of Genbank in order to pick any hIgG4 Fc region suitable for a flagellin fusion protein as taught by KR20080074556 and KR20190095946 . There is a reasonable expectation of success given that hIgG4 Fc regions are known in the art and comprise variations of KR20190095946 which are known to be therapeutically safe and provide for the benefits as described therein.
Claims 1-4, 6-15, 18, and 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over KR20080074556 (cited on IDS, English copy provided herein) in view of KR20190095946 (cited on IDS, google translation provided herein) and further in view of Chen et al. (“Fusion protein linkers: property, design and functionality” Adv Drug Deliv Rev. PMC Oct 2014).
The teachings of KR20080074556 and KR20190095946 are presented in detail above.
The references as combined do not teach the sequence of Fc region and the flagellin are lined by a linker that consist of SEQ ID NO:12.
Chen et al. teach that linkers are an indispensable component of fusion proteins and have shown increasing importance in the construction of stable, bioactive fusion proteins. Chen et al. teach many protein drugs are fused to Fc region (1st para of Introduction). Chen et al. teach the most commonly used linkers are GS linkers , such as (GGGGS)n, wherein n can be optimized to achieve the appropriate separation of the functional domains or to maintain necessary inter-domain interactions (2nd para. of 3.1 Flexible linkers section). Table 3 discloses linkers that meet the limitations of SEQ ID NO: 8 and 9.
It would have been obvious to optimize the function of the flagellin fusion by using the the GS linkers of Chen et al. because Chen et al. teach GS linkers can be optimized to achieve the appropriate separation of the function domains or to maintain the necessary inter-domain interactions. There is a reasonable expectation of success given that the art provides that such likers are common in linking protein domains in fusion proteins and GS linkers are routinely used in the art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Patricia Duffy whose telephone number is (571)272-0855. The examiner can normally be reached 8:00 am - 4 pm.
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/Patricia Duffy/Primary Examiner, Art Unit 1645
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