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 .
This action is in response to the papers filed on 05/18/2026. Claims 1, 4-8, 14-17, 25-31 are currently pending as per claims filed on 05/18/2026. Claim 1 has been amended, claims 25-31 are newly added and claims 2-3 and 19-20 have been canceled by applicants’ amendment filed on 05/18/2026. New claims 25-26 and 28-31 have been withdrawn from consideration by applicants’ amendment filed on 05/18/2026.
Applicant’s election without traverse of Group I, claims 1, 4-8, 14-17 in the reply filed on 05/18/2026 is acknowledged.
Applicant asserts that the restriction requirement did not address claim 18. Examiner notes that Claim 18 was cancelled per preliminary amendment of claims filed 08/31/2023.
Newly added claim 27, depends from claim 17 and claim 17 reads on the elected Group I, therefore claim 17 is being considered. Claims 25, 26, and 28-31 are withdrawn from consideration as being drawn to non-elected inventions.
The requirement is still deemed proper and is therefore made FINAL.
Therefore, claims 1, 4-8, 14-17 and 27 are examined on their merits to which the
following grounds of rejection are applicable. Claims 1 is an independent claim.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2022/007612 filed on 02/24/2022, which claims priority to Japanese Application 2021 031757, filed March 1, 2021. Filing of a certified untranslated copy of the Japanese Application 2021 031757, filed August 31, 2023 is acknowledged.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
.
Thus, the earliest possible priority for the instant application is March 1, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/31/2023, 10/17/2024, 06/26/2025, and 10/06/2025 were filed after the mailing date of the current office action. The submission is in compliance with the provisions of 37 CFR 1.97.
Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 1, 4-8, 14-17 are objected to because abbreviations such as FcɛRI should be spelled out at the first encounter in the claims. Appropriate correction is required
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 17 and 27 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 17 recites “the chimeric FcɛRI α-chain produced based on the chimeric FcɛRI α-chain gene and the γ-chain of the FcɛRI of the cell”. It is unclear what exactly is being “produced based on” the chimeric FcɛRI α-chain gene as it could be the mRNA or protein. Claim 27 inherits these deficiencies insofar as it depends of claim 17.
Claim 17 is indefinite in its recitation of “the y-chain of FcɛRI of the cell”. There is not proper antecedent bases for “the y-chain of FcɛRI of the cell” in the claim. As such the metes and bounds of the claim are indefinite.
Claim 27 is indefinite in its recitation of “the complexes”. There is not proper antecedent bases for “the complexes” in the claim. As such the metes and bounds of the claim are indefinite.
Claim Interpretation
Claim 17 recites “the chimeric FcɛRI α-chain produced based on the chimeric FcɛRI α-chain gene and the γ-chain of the FcɛRI of the cell”. It is interpreted that the chimeric FcɛRI α-chain produced is the polypeptide that is translated from the chimeric FcɛRI α-chain gene such that it can complex with the γ-chain of the FcɛRI of the non-human animal cell. It is suggested that applicant amend claim to be explicit on what exactly is being “produced”.
Claim Rejections - 35 USC § 112 (a)
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.
Claim 1, 4-8, 14-17, and 27 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 Federal Circuit has clarified the written description requirement. The court stated that a written description of an invention "requires a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials". University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568; 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). The court also concluded that "naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not description of that material". Id. Further, the courtheld that to adequately describe a claimed genus, Patent Owner must describe a representative number of the species of the claimed genus, and that one of skill in the art should be able to "visualize or recognize the identity of the members of the genus".
The claims are drawn to a chimeric FcɛRIα-chain gene comprising:
a first base sequence encoding an extracellular domain of a human FcɛRIα-chain
a second base sequence encoding at least a transmembrane domain of a non-human animal FcɛRIα -chain,
wherein the first base sequence comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 7
wherein the second base sequence comprises at least a base sequence having 70% or more sequence identity with SEQ ID NO: 5.
the second base sequence further comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 6. (claim 4)
A third base sequence comprising a base sequence having 70% or more sequence identity with SEQ ID NO: 2. (claim 6)
wherein the chimeric FcɛRIα -chain gene has a base sequence having 50% or more sequence identity with SEQ ID NO: 1. (claim 7)
Formation of a complex comprising the chimeric FcɛRIα -chain produced based on the chimeric FcɛRIα -chain gene and the y-chain of FcɛRI (claim 17)
With the exception of 7 constructs ("HuRa-11", "HuRa-19", "HuRa-21", "HuRa-29", "HuRa-37", "HuRa-38", and "HuRa-40" (specification Figure 7, para 0212) encoding the entire chimeric FcɛRIα -chain gene, all of which are interpreted to be the full sequence set forth in SEQ ID NO: 1 as the specification only discloses that the examples are of SEQ ID NO: 1 (para 0186, para 0193, para 0205, and Figure 4), the Applicant’s do not describe a representative number of species of the broadly claimed genus of first, second, and third base sequences each with 70% or more sequence identity to SEQ ID NO: 7, SEQ ID NO: 5/6, and SEQ ID NO: 2, respectively. Similarly, Applicant’s do not describe a representative number of species of the broadly claimed genus of chimeric FcɛRIα -chain gene that has a base sequence having 50% or more sequence identity to SEQ ID NO: 1 (claim 7) . Rather, the specification only provides working examples of generating 7 constructs comprising a chimeric FcɛRIα -chain gene and wherein the chimeric FcɛRIα -chain gene comprises the full nucleotide sequence of SEQ ID NO:1 and demonstrate the ability to induce a reporter gene (luciferase). Indeed, SEQ ID NO: 1 comprises, as shown in Figure 19 below:
The first base sequence (extracellular domain) set forth in SEQ ID NO: 7 which functions as an IgE binding region (para 0041)
The second base sequence (transmembrane domain) set forth in SEQ ID NO: 5 which functions as a γ-chain binding domain (para 0049)
The second base sequence further comprising sequence set forth in SEQ ID NO: 6 (intracellular domain) and,
A third base sequence set forth in SEQ ID NO: 2 (signal sequence)
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red = SEQ ID NO: 2, purple = SEQ ID NO: 7, green = SEQ ID NO: 5, yellow = SEQ ID NO: 6
With the exception of the full-length chimeric FcɛRIα encoded by the chain gene of SEQ ID NO:1 and its components (including extracellular domain set forth in SEQ ID NO: 7, transmembrane domain set for in SEQ ID NO: 5, intracellular domain set forth in SEQ ID NO: 6, and signal sequence set forth in SEQ ID NO: 2), Applicants have not described any other polynucleotides which have at least 50% identity to SEQ ID NO:1 and 70% identity to any of the nucleotides identified by the SEQ IDs for each respective component of the chimeric FcɛRIα -chain gene and which, when expressed in all possible cells, confer the phenotype of complexing with the γ-chain of the FcɛRI cell and inducing expression of a reporter gene when complexed/crosslinked. Applicants fail to specifically describe any other possible polynucleotide from the broadly claimed genus of polynucleotides having at least 50% identity to SEQ ID NO:1 and 70% identity to the SEQ IDs for each respective component of the chimeric FcɛRIα -chain gene such that it would the confer the phenotype of complexing with the γ-chain of the FcɛRI cell and inducing expression of a reporter gene when complexed/crosslinked in all cells. This disclosure is not deemed to be descriptive of the complete structure of a representative number of species encompassed by the claims as one of skill in the art cannot envision all the fragments having complexing with the γ-chain of the FcɛRI cell and inducing expression of a reporter gene when complexed/crosslinked in the cell based on the teachings in the specification. The specification does not teach regions or domains of the protein that are essential for the claimed activity. There is not structure/function relationship taught at all for SEQ ID No. 1.
As discussed in MPEP 2163(I)(A), “a biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence”
Moroever, the instant Specification fails to provide guidance for which nucleotides of SEQ ID NO:1, 2, 5, 6, and 7 can be substituted, and to which nucleotides, and also which nucleotides must not be changed, to maintain the functional activity of the encoded gene. The Specification also fails to provide guidance for which nucleotides can be deleted and which regions of the gene can tolerate insertions and/or additions and still produce a functional protein. Describing and reducing to practice the claimed genus of nucleotide substitutions/deletions/insertions in the gene of SEQ ID NO:1, 2, 5, 6, and 7 is unpredictable. While it is known that many nucleotide substitutions, additions or deletions are generally possible in any given gene, the positions within the gene’s sequence where the resulting amino acid changes can be made with a reasonable expectation of success (without altering protein function) are limited. Certain positions in the sequence are critical to the protein’s structure/function. (see Ngo, in The Protein Folding Problem and Tertiary Structure Prediction, Merz et al. (eds.), Birkhauser Boston: Boston, MA, pp. 433 and 492-495, 1994). Rudinger (in Peptide Hormones, Parsons (ed.), University Park Press: Baltimore, MD, pp. 1-7, 1976) discloses that even for peptide hormones, which are much smaller than the instant FcɛRI α-chain, one cannot predict variant amino acid sequences for a biologically active polypeptide. As an example, related to sequence modifications for Fc receptor genes, it is known that a single nucleotide change in exon 4 in FcγRIIa gene leads to an arginine (R) to histidine (H) change and can alter the receptor affinity for its ligand, thus altering its functionality. Similarly, some SNPs in the FcR cluster can affect the signaling capacity of the expressed receptor (see Human FcR Polymorphism and Disease, Li, 2014, page 276 and 281).
To put the situation in perspective, claim 7 recites any gene that is 50% similar to the base sequence of SEQ ID NO:1 (SEQ ID NO: 7 is 741 base pairs). That 50 percent variance results in a situation in which even if a 371 contiguous nucleotide region is independently varied among the 4 different nucleotides (3714), there would be 18,945,044,881 possible combinations. In fact, since the variation could occur at any position, the actual number of different molecules is orders of magnitude greater than 18,945,044,881. Thus, the Specification fails to overcome the unpredictability of reducing to practice the large numbers of nucleotide deletions/substitutions/insertions/additions in the gene of SEQ ID NO:1, 2, 5, 6, and 7 and still retain the contemplated function as it does not provide an adequate description of the gene with the recited nucleotide substitutions relative to SEQ ID NO:1, 2, 5, 6, and 7 and there is an extremely large genus of possible combinations for just SEQ ID NO:1.
The Specification fails to provide an adequate written description to support the breadth of the claims as only one chimeric FcɛRI α-chain gene is disclosed (SEQ ID NO: 1). Therefore, the specification does not describe the claimed fragments in such full, clear, concise and exact terms so as to indicate that Applicant has possession of these fragments at the time of filing the present application. Thus, it is concluded that the written description requirement is not satisfied for the claimed genera.
Scope of Enablement
Claim 1, 4-8, 14-17, and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
a chimieric FcɛRI α-chain gene comprising a sequence set forth in SEQ ID NO: 1 which comprises:
The first base sequence (extracellular domain) set forth in SEQ ID NO: 7 which functions as an IgE binding region (para 0041)
The second base sequence (transmembrane domain) set forth in SEQ ID NO: 5 which functions as a γ-chain binding domain (para 0049)
The second base sequence further comprising sequence set forth in SEQ ID NO: 6 (intracellular domain) and,
A third base sequence set forth in SEQ ID NO: 2 (signal sequence)
does not reasonably provide enablement for:
the first base sequence comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 7
wherein the second base sequence comprises at least a base sequence having 70% or more sequence identity with SEQ ID NO: 5.
the second base sequence further comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 6.
A third base sequence comprising a base sequence having 70% or more sequence identity with SEQ ID NO: 2.
wherein the chimeric FcɛRIα -chain gene has a base sequence having 50% or more sequence identity with SEQ ID NO: 1.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
the breadth of the claims; the nature of the invention:
The claims are drawn to a vast genus of chimeric FcɛRIα-chain genes comprising a first base sequence comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 7, a second base sequence comprises at least a base sequence having 70% or more sequence identity with SEQ ID NO: 5 and further comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 6, A third base sequence comprising a base sequence having 70% or more sequence identity with SEQ ID NO: 2, and wherein the chimeric FcɛRIα -chain gene has a base sequence having 50% or more sequence identity with SEQ ID NO: 1.
The claims broadly encompass any nucleotide substitution/deletion/insertion for the chimeric FcɛRI-α chain gene such that there is at least 70% or more identity to SEQ ID NO: 2, 5, 6, and 7 and at least 50% or more indentity to SEQ ID NO: 1 and such that the chimeric FcɛRI-α chain gene can perform the claimed function of complexing with the γ-chain of the FcɛRI of the cell. Thus. The claims are directed to a large genus of chimeric FcɛRI-α chain genes that could comprise a vast array of nucleotide sequences that result in a gene product capable of complexing the the γ-chain of FcɛRI and induce expression of any reporter gene in any cell.
the amount of direction provided by the inventor; the existence of working examples:
However, the specification does not disclose a reduction to practice of chimeric FcɛRI-α chain gene other than a chimeric FcɛRI-α chain gene sequence set forth in SEQ ID NO: 1, which comprises the components: extracellular domain set forth in SEQ ID NO: 7, transmembrane domain set for in SEQ ID NO: 5, intracellular domain set forth in SEQ ID NO: 6, and signal sequence set forth in SEQ ID NO: 2. The specification does not disclose if any other nucleotide sequences, besides those aforementioned, would permit the translation of the corresponding protein sequence of the FcɛRI-α chain gene and thus exhibit the phenotype of complexing with the γ-chain of FcɛRI and inducing reporter gene expression in any cell. The specification only contemplates that the chimeric FcɛRI-α chain with at least 70% or more identity to SEQ ID NO: 2, 5, 6, and 7 and at least 50% or more identity to SEQ ID NO: 1 can perform the claimed function of complexing with the γ-chain of the FcɛRI of the cell and inducing reporter gene expression in any cell.
the state of the prior art; the level of predictability in the art:
It is known in the art that even conservative amino acid substitutions, which ultimately arise from modifications of a corresponding nucleic acid sequence, can adversely affect proper folding and biological activity if amino acids that are critical for such functions are substituted, and the relationship between the sequence of a polypeptide and its tertiary structure is neither well understood nor predictable (see Ngo, in The Protein Folding Problem and Tertiary Structure Prediction, Merz et al. (eds.), Birkhauser Boston: Boston, MA, pp. 433 and 492-495, 1994). Rudinger (in Peptide Hormones, Parsons (ed.), University Park Press: Baltimore, MD, pp. 1-7, 1976) discloses that even for peptide hormones, which are much smaller than the instant FcɛRI α-chain, one cannot predict variant amino acid sequences for a biologically active polypeptide. Rather one must engage in "case to case painstaking experimental study" to determine active variants (see page 7). It is known that Human Fc receptor polymorphisms exist and the vast array of polymorphisms have functional implications. For example, a single nucleotide polymorphisms (SNP) in exon 4 in FcγRIIa gene leads to an arginine (R) to histidine (H) change and can alter the receptor affinity for its ligand, thus altering its functionality. Similarly, some SNPs in the FcR cluster can affect the signaling capacity of the expressed receptor (see Human FcR Polymorphism and Disease, Li, 2014, page 276 and 281).
Hence, modifications in the sequence corresponding to the FcɛRI-α chain gene, including all of its components, and corresponding phenotype of complexing with the γ-chain and inducing reporter gene expression in a cell is not necessarily predictable.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The skilled artisan would be required to perform under levels of experimentation in order to practice the claimed invention. The instant specification does not reduce to practice the claimed invention; the instant specification does not provide guidance on how to reasonably predict which nucleotides for each of the SEQ ID NOs 1, 2, 5, 6, and 7 should be mutated to gain the desired phenotype of complexing the FcɛRIα-chain with the γ-chain and inducing reporter gene expression upon complexing. Excessive trial and error experimentation would have been required to identify the necessary derivatives for the entire FcɛRI-α chain gene with an activity of SEQ ID NO: 1, as well as the activity for the derivatives for each of the FcɛRI-α chain gene components (i.e. SEQ ID 2, 5, 6, and 7) and since the amino acid sequence resulting from the polynucleotide sequences could not be predicted - even were the activity known.
The level of one of ordinary skill:
The level of one of ordinary skill is a PhD holder.
Conclusion
When all of the Wands factors are considered together, they establish a prima facie case that the specification is not enabling for the claims. The specification only provides details for the FcɛRI-α chain gene corresponding to SEQ ID NO:1, which comprises the components: SEQ ID NO: 2, 5, 6, and 7, and which can form a complex with the γ-chain and induce reporter gene expression function in a cell. While a lack of a working embodiment cannot be a sole factor in determining enablement, the lack of any working examples, in light of the unpredictable nature of the art and the lack of direction applicants present, provides additional weight to the lack of enablement in consideration of the Wands factors as a whole. Thus, one of ordinary skill in the art would not have had a reasonable expectation of success in making or using the claimed invention.
Claim Rejections - 35 USC § 103
To the extent that the claims are broadly directed to nucleotide fragments having at least 70% sequence identity with the nucleotide sequences identified as SEQ ID NO:1, 2, 5, 6, and 7, the following rejection applies.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 4-8, 14-17, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Dombrowicz et al (The Journal of Immunology, 1996, pages 1645-1651) and further in view of Macdonald et al (PNAS, 2014, pages 5147–5152), Jang et al (WO 2022019652 A1), Senoo et al (JP 2009050182 A), Kinet et al (Biochemistry, 1987, pages 4605-4610), Platzer et al (The Journal of Biological Chemistry, 2010, pages 15314-15323), Chakraborty et al (US 9220755 B2), and Nakamura et al (JP 2011019467 A; as cited in IDS).
The applied Nakamura reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Nakamura is 02/03/2011. The earliest effective filing date of the instant application is 03/01/2021. Therefore rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claim 1, Dombrowicz teaches a transgene construct comprising a sequence for the full human FcɛRI α-chain gene (i.e. including the extracellular domain) that is integrated into the genome of a mouse cell such that the mouse FcɛRI α-chain gene has been replaced with the human FcɛRI α-chain gene (page 1645, right col, para 2-3). Dombrowicz teaches a need to increase the usefulness of the mouse as a model system for understanding human immune responses and that it would therefore be desirable to create mice in which the immune system more closely resembles that of humans (page 1645, left col, para 1). Dombrowicz teaches the introduction of the transgene construct into the mouse genome would “help develop better models for the study of anaphylaxis and allergic responses jn vivo” (page 1645, right col, para 2-3). Hence, Dombrowicz renders obvious a chimeric FcɛRI α-chain gene comprising a first base sequence encoding an extracellular domain of a human FcɛRI α-chain.
Dombrowicz does not teach a second base sequence encoding at least a transmembrane domain of a non-human animal FcɛRI α-chain.
Macdonald teaches that “the most effective humanization of transmembrane targets will often be to generate a chimeric gene in which the genomic region encoding
the extracellular domain is humanized and fused within an intron to mouse genomic sequences encoding the transmembrane and intracellular regions.” (page 5151, right col, para 2).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a human FcɛRI α-chain gene from Dombrowicz to replace the human transmembrane domain and replace it with a mouse transmembrane domain, as taught by Macdonald to generate a chimeric FcɛRI α-chain with a human extracellular domain and a mouse transmembrane domain. One would be motivated to do so as Macdonald taught that this approach is the most effective method to humanize transmembrane targets, such as FcɛRI α-chain gene encoding an extracellular domain of a human FccRI a-chain and therefore would improve the outcome of generating functional chimeric genes, especially if one is interested developing useful mouse models as taught by Dombrowicz. As generating chimeric genes with humanized extracellular domains and non-human animal transmembrane domains is known in the art, one would have a reasonable expectation of success.
The combined teachings of Dombrowicz and Macdonald do not teach wherein the first base sequence comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 7.
Jang et al teaches a human FcεRIα extracellular domain having the sequence of SEQ ID NO: 7 which has 85.1% alignment to SEQ ID NO: 7 of the instant application. Thus, Jang renders obvious wherein the first base sequence comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 7.
See alignment below:
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415
660
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Qy = instant application SEQ ID NO: 7; Db = SEQ ID NO: 7 of Jang
The combined teachings of Dombrowicz, Macdonald, and Jang do not teach wherein the second base sequence encoding at least a transmembrane domain of a non-human animal FccRI a-chain comprises at least a base sequence having 70% or more sequence identity with SEQ ID NO: 5.
Senoo teaches a cell surface marker gene probe that detects the transmembrane region of a cell surface protein (I.e. a FcεRIα) that comprises the sequence set forth in SEQ ID NO: 2073 which has 77.2% identity to SEQ ID NO: 5 of the instant application, hence rendering obvious the second base sequence comprises at least a base sequence having 70% or more sequence identity with SEQ ID NO: 5. See sequence alignment below:
Qy = instant application SEQ ID NO: 7; Db = SEQ ID NO: 2073 of Senoo
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174
631
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Regarding claim 4, the teachings of Dombrowicz, Macdonald, Jang, and Senoo render obvious claim 1.
The combined teachings of Dombrowicz, Macdonald, Jang, and Senoo do not teach wherein the second base sequence further comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 6.
Kinet teaches a nucleic acid sequence for a rat receptor with high affinity for immunoglobulin E, alpha subunit (i.e. FcεRIα) that has 80.6% sequence identity to the SEQ ID NO: 6 of the instant application, hence rendering obvious the second base sequence further comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 6. See sequence alignment below:
Qy = instant application SEQ ID NO: 6; Db =
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243
665
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Kinet
Regarding claim 5, the teachings of Dombrowicz, Macdonald, Jang, and Senoo render obvious claim 1.
The combined teachings of Dombrowicz, Macdonald, Jang, and Senoo do not teach wherein the chimeric FcεRIα -chain gene further comprises a third base sequence encoding a signal sequence for expressing, on the cell membrane, the chimeric FcsRI a-chain generated based on the gene.
Platzer teaches that “the Type I membrane proteins, including FcεRIα, contain a short cleavable N-terminal sequence called the signal peptide. The signal peptide sequence assures proper translocation into the ER; it binds the signal recognition particle and later is cleaved on the endoplasmic reticulum (ER) luminal side by signal peptidases”. (page 15315, left col, para 1). Platzer teaches that “the endogenous signal peptide of FcεRIα does indeed contain a regulatory element that controls ER exit and consecutively cell surface expression of this protein”.
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a chimeric FcεRIα -chain gene comprising a first sequence for the extracellular domain of a human FcεRIα and second sequence for the transmembrane domain of a non-human animal FcεRIα chain as collectively taught by Dombrowicz, Macdonald, Jang, and Senoo to additionally have a third base sequence for a signal sequence as Platzer teaches that the signal sequence is important for proper translocation into the ER, exit from the ER, and ultimately cell surface expression. One would be motivated to combine to do so to ensure the FcεRIα-chain chimeric gene is most effectively and properly expressed by the cell. As generation of a FcεRIα-chain chimeric gene and its corresponding signal peptide are known in the art, one would have a reasonable expectation of success.
Regarding claim 6, teachings of Dombrowicz, Macdonald, Jang, Senoo, and Platzer render obvious claim 1 and 5.
The combined teachings of Dombrowicz, Macdonald, Jang, Senoo, and Platzer do not teach wherein the third base sequence comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 2.
Chakraborty teaches polynucleotide constructs which may comprise one or more signal sequences encoded by a signal sequence region (para 25, Fig 1). Chakraborty teaches a polynucleotide construct with a sequence set for in SEQ ID NO: 223082 and has 84% identity to SEQ ID NO: 2 of the instant application, hence rendering obvious wherein the third base sequence comprises a base sequence having 70% or more sequence identity with SEQ ID NO: 2. See sequence alignment below:
Qy = instant application SEQ ID NO: 2; Db = Chakraborty SEQ ID NO: 223082
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Regarding claim 7, the teachings of Dombrowicz, Macdonald, Jang, and Senoo render obvious claim 1.
The combined teachings of Dombrowicz, Macdonald, Jang, and Senoo do not teach wherein the chimeric FcεRIα -chain gene has a base sequence having 50% or more sequence identity with SEQ ID NO: 1.
Chakraborty teaches polynucleotide constructs which may comprise one or more signal sequences encoded by a signal sequence region (para 25, Fig 1). Chakraborty teaches a polynucleotide construct with a sequence set for in SEQ ID NO: 81490 and has 79.8% identity to SEQ ID NO: 1 of the instant application, hence rendering obvious wherein the chimeric FcεRIα -chain gene has a base sequence having 50% or more sequence identity with SEQ ID NO: 1. See sequence alignment on the next page:
Qy = instant application SEQ ID NO: 2; Db = Chakraborty SEQ ID NO: 223082
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Regarding claim 8, the teachings of Dombrowicz, Macdonald, Jang, and Senoo render obvious claim 1. Moreover, Macdonald teaches a mouse genomic sequences encoding the transmembrane and intracellular regions (page 5151, right col, para 2), rendering obvious wherein the non-human animal transmembrane domain is a rodent animal.
Regarding claim 14, the teachings of Dombrowicz, Macdonald, Jang, and Senoo render obvious claim 1. Moreover, Dombrowicz teaches a vector comprising a human FcεRIα fragment (page 1646, left col, Materials and Methods, para 1), rendering obvious a vector comprising the chimeric FcεRIα -chain gene according to claim 1.
Regarding claim 15, the teachings of Dombrowicz, Macdonald, Jang, and Senoo render obvious claim 1. Moreover, Dombrowicz teaches an embryonic stem cell of a mouse comprising a fragment containing the human FcεRIα gene (page 1646, left col, Materials and Methods, para 2), rendering obvious a cell of a non-human animal comprising the chimeric FcsRIa-chain gene according to claim 1.
Regarding claim 16 and 17, the teachings of Dombrowicz, Macdonald, Jang, and Senoo render obvious claim 1. Moreover, Dombrowicz teaches that, within the mouse (i.e. the cells of the mouse), their human FcεRIα protein was able to form a complex with mouse β- and γ- FcεRI (page 1648, left col, para 1), rendering obvious the cell further comprising a gene of the y-chain of FcεRI of the non-human animal cell (claim 16) and a complex comprising the chimeric FcεRIα -chain produced based on the chimeric FcsRI a-chain gene and the y-chain of FcεRI of the cell.
Regarding claim 27, the teachings of Dombrowicz, Macdonald, Jang, and Senoo render obvious claim 1, 15, 16, and 17.
The combined teachings of Dombrowicz, Macdonald, Jang, and Senoo do not teach the cell according to claim 17, further comprising a reporter gene whose expression is induced by cross-linking between the complexes.
Nakamura teaches a method of testing allergens for a test subject involving incubating a cell having a human IgE-affinity Fc receptor on the cell membrane and the cell having a reporter gene. Nakamura teaches that when a test substance is contacted with the cell, crosslinking occurs between multiple Fc receptors on the cells, activating a specific transcription factor which in turn promotes the expression of the reporter gene. Nakamura teaches that “By confirming the increased expression of this reporter gene, it is possible to test whether the test substance is an allergen to the subject” (page 9, para 5, line 29-34).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a cell comprising a chimeric FcεRIα -chain gene and a FcɛRI γ-chain taught by Dombrowicz, Macdonald, Jang, and Senoo to have a cell that further comprises a reporter gene that is expressed upon crosslinking of the chimeric FcεRIα -chain gene and a FcɛRI γ-chain and creating a complex to ultimately generate a cell that can report the extracellular binding of an antigen onto the chimeric FcεRIα -chain gene via expression of the reporter gene such as luciferase. One would be motivated to do so to generate a cell that can be used to test allergen sensitivity as the cell is able to express a reporter gene upon contact and activation of the chimeric FcεRI. As cells comprising the chimeric FcεRI and reporter genes have been shown in the art, one would have a reasonable expectation of success.
Conclusion
Claims 1, 4-8, 14-17 and 27 are rejected.
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/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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