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 .
Applicants’ amendment to the claims filed on 6/9/2023 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 1-2 are pending and examined on the merits.
Priority
Acknowledgement is made of this continuation application of Non-provisional Application No. 18/332,889, filed on 6/9/2023, which claims foreign priority under 35 U.S.C. 119(a)-(d) to Chinese Patent Application No. CN202210685070X, filing date 6/16/2022. The certified copy has been filed in the present application on 07/22/2023. 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.
Drawings
The Drawings filed on 6/9/2023 are acknowledged and accepted by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: recitation of ‘20 Celsius degree (℃).’ It is recommended that Applicant amend the claim to recite ‘20 degrees Celsius (℃)’ or ‘20℃.’ Appropriate correction is suggested.
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.
Claims 1-2 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation ‘a prokaryotic cell,’ and the claim also recites ‘a host bacterium’ which is the narrower statement of the range/limitation. A ‘prokaryotic cell’ is inclusive of bacteria and archaea. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 1 (claim 2 dependent thereof), the phrase " an amino acid sequence of the recombinant IL-18BP is shown in SEQID NO:" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. It is unclear if the claim encompasses fragments, full length, etc. of the sequences. It is also recommended that Applicant amend claim 1 from ‘an amino acid sequence of the recombinant IL-18BP is shown in SEQID NO’ to ‘the amino acid sequence of the recombinant IL-18BP the amino acid sequence of the molecular chaperone Sumo
In order to practice compact prosecution, it is also recommended that Applicant amend claim 1 to recite ‘an amino acid sequence of the molecular chaperone Sumo
Written Description
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 1-2 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.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claims 1-2 are drawn to a method for fermenting and producing a recombinant interleukin-18 binding protein (IL-18BP), comprising: inducing fermentation to culture a host bacterium to obtain the recombinant interleukin-18 binding protein; wherein expression conditions for the inducing with isopropyl-β-D-thiogalactoside (IPTG) are as follows: induction at 0.5 millimoles per liter (mmol/L) IPTG at 20 Celsius degree (℃) for 4-31 hours; wherein the recombinant IL-18BP is prepared as follows: connecting a 5’ end of a coding gene of the recombinant IL-18BP with a gene sequence of a molecular chaperone Sumo to construct a fusion gene, inserting the fusion gene into a cell expression vector, and guiding the cell expression vector into a prokaryotic cell to express the recombinant IL-18BP; wherein the recombinant IL-18BP comprises a sequence encoding human IL-18BP isoform a (hIL‑18BPa) and a sequence encoding human immunoglobulin class G-crystallizable fragment (IgG-Fc); an amino acid sequence of the recombinant IL-18BP is shown in SEQ ID NO: 1, a nucleotide sequence of the coding gene of the recombinant IL-18BP is shown in SEQ ID NO: 3; and an amino acid sequence of the molecular chaperone Sumo is shown in SEQ ID NO: 2. The structure of ‘an amino acid sequence of the recombinant IL-18BP is shown in SEQ ID NO: 1’ and ‘an amino acid sequence of the molecular chaperone Sumo is shown in SEQ ID NO: 2’ is a large number of sequences and encompasses fragments comprised of at least 2 contiguous bases.’ It’s suggested that Applicant amend the claim to recite ‘the amino acid sequence of seq id no: ‘ to overcome the rejection.
In this case, the specification discloses IL-18BP isoform A with IgG and synthetic molecular chaperone SUMO as encompassed by the claims (i.e. SEQ ID NO: 1 is hIL-18BP isoform A with IgG; SEQ ID NO: 2 is molecular chaperone SUMO). Other than the above disclosed species, there is no prior-art or disclosed teaching as to the large number of sequences that encompass at least 2 contiguous bases with homology to SEQ ID NO: 1 and SEQ ID NO: 2 for fermenting and producing recombinant IL-18BP and molecular chaperone SUMO. The breadth of the claims encompass sequence with at least 2 contiguous bases with homology to SEQ ID NO: 1 and 2 through genetic modification of genes encoding proteins or post-translational modifications, etc. via any modification technique such as deletion, mutation, etc. for fermenting and producing recombinant IL-18BP and molecular chaperone SUMO.
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004). Here, the disclosure fails to teach all recombinant IL-18BP and molecular chaperone SUMO for fermenting and producing a recombinant interleukin-18 binding protein (IL-18BP).
Accordingly, one of skill in the art would not accept the disclosure of SEQ ID NO: 1 and SEQ ID NO: 2 as being representative of all recombinant IL-18BP and molecular chaperone SUMO as encompassed by the claims. As such, the specification, taken with the pre-existing knowledge in the art of expression vectors, fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph.
Scope of Enablement
Claims 1-2 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 recombinant IL-18BP (SEQ ID NO: 1) and a molecular chaperone SUMO (SEQ ID NO: 2) for fermenting and producing a recombinant IL-18BP, it does not reasonably provide enablement for all recombinant IL-18BP and molecular chaperone SUMO as encompassed by the claims. 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 test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (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. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
(A)The breadth of the claims:
Claims 1-2 are drawn to a method for fermenting and producing a recombinant interleukin-18 binding protein (IL-18BP), comprising: inducing fermentation to culture a host bacterium to obtain the recombinant interleukin-18 binding protein; wherein expression conditions for the inducing with isopropyl-β-D-thiogalactoside (IPTG) are as follows: induction at 0.5 millimoles per liter (mmol/L) IPTG at 20 Celsius degree (℃) for 4-31 hours; wherein the recombinant IL-18BP is prepared as follows: connecting a 5’ end of a coding gene of the recombinant IL-18BP with a gene sequence of a molecular chaperone Sumo to construct a fusion gene, inserting the fusion gene into a cell expression vector, and guiding the cell expression vector into a prokaryotic cell to express the recombinant IL-18BP; wherein the recombinant IL-18BP comprises a sequence encoding human IL-18BP isoform a (hIL‑18BPa) and a sequence encoding human immunoglobulin class G-crystallizable fragment (IgG-Fc); an amino acid sequence of the recombinant IL-18BP is shown in SEQ ID NO: 1, a nucleotide sequence of the coding gene of the recombinant IL-18BP is shown in SEQ ID NO: 3; and an amino acid sequence of the molecular chaperone Sumo is shown in SEQ ID NO: 2. The structure of ‘an amino acid sequence of the recombinant IL-18BP is shown in SEQ ID NO: 1’ and ‘an amino acid sequence of the molecular chaperone Sumo (synthetic) is shown in SEQ ID NO: 2’ is a large number of sequences and encompasses fragments comprised of at least 2 contiguous bases.’ It is suggested that Applicant amend the claim to recite ‘the amino acid sequence of seq id no: ‘ to overcome the rejection.
B) The nature of the invention; C)The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: As noted above, the scope of the claimed SEQ ID NO: 1 and 2 are a large number of sequences as they encompass structures with at least 2 contiguous bases. As such, the structure of the claimed SEQ ID NO: 1 (recombinant IL-18BP) and SEQ ID NO: 2 (molecular chaperone SUMO) are a large number of sequences.
It is well-known in the prior art that the amino acid sequence of a polypeptide determines the polypeptide’s functional properties. The positions within a protein's sequence where modifications can be made with a reasonable expectation of success in obtaining a polypeptide having the desired activity/utility are limited in any protein and the result of such modifications is highly unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g., multiple substitutions. The reference of Singh et al. (Current Protein and Peptide Science, 2017; examiner cited) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes [see p. 7, column 1, top]. The reference of Zhang et al. (Structure, 2018; examiner cited) discloses that a mutation of a residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide [p. 1475, column 1].
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working examples of recombinant IL-18BP and molecular chaperone SUMO (i.e. SEQ ID NO: 1 (recombinant IL-18BP) and SEQ ID NO: 2 (molecular chaperone SUMO)). Other than the above disclosed species, there is no prior-art or disclosed teaching as to the large number of cell sequences that encompass a recombinant IL-18BP and molecular chaperone SUMO. Other than the working example, the specification fails to disclose any other working examples of a recombinant IL-18BP and molecular chaperone SUMO for fermenting and producing a recombinant IL-18BP.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (Date Published: 2010, Hybridoma, Examiner cited) {herein Lee} in view of Zhang et al (2014, Appli Microbiol Biotechnol, Examiner cited) {herein Zhang} and evidenced by Butt et al (2005, protein expression & purification, Examiner cited) {herein Butt}.
Claims 1-2 are drawn to a method for fermenting and producing a recombinant interleukin-18 binding protein (IL-18BP), comprising: inducing fermentation to culture a host bacterium to obtain the recombinant interleukin-18 binding protein; wherein expression conditions for the inducing with isopropyl-β-D-thiogalactoside (IPTG) are as follows: induction at 0.5 millimoles per liter (mmol/L) IPTG at 20 Celsius degree (℃) for 4-31 hours; wherein the recombinant IL-18BP is prepared as follows: connecting a 5’ end of a coding gene of the recombinant IL-18BP with a gene sequence of a molecular chaperone Sumo to construct a fusion gene, inserting the fusion gene into a cell expression vector, and guiding the cell expression vector into a prokaryotic cell to express the recombinant IL-18BP; wherein the recombinant IL-18BP comprises a sequence encoding human IL-18BP isoform a (hIL-18BPa) and a sequence encoding human immunoglobulin class G-crystallizable fragment (IgG-Fc); an amino acid sequence of the recombinant IL-18BP is shown in SEQ ID NO: 1, a nucleotide sequence of the coding gene of the recombinant IL-18BP is shown in SEQ ID NO: 3; and an amino acid sequence of the molecular chaperone Sumo is shown in SEQ ID NO: 2.
With respect to claim 1, Lee teaches a method of producing a recombinant IL-18BP isoform A cloned within a pLysE vector and transformed within an E. coli host cell and cultured in LB broth (page 518, column 1, para 3, 4). Absent evidence otherwise, it is the Examiner’s opinion that the IL-18BP isoform A, taught by Lee is the same as the IL-18BP isoform A recited in claim 1 of the instant application as both recombinant proteins function in binding IL-18 (page 517, column 1, para 1). Furthermore, Examiner is interpreting the recitation of ‘fermenting’ (instant application claim 1) as the same as culturing as both processes result in cellular growth. Said recombinant protein was induced by IPTG (page 518, column 1, para 4). Although the reference of Lee does not explicitly teach the limitations of claim 1, ‘induction at 0.5 millimoles per liter (mmol/L) IPTG at 20 Celsius degree (℃) for 4-31 hours,’ MPEP 2144.05 states"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05 IIA)." One of ordinary skill in the art would desire to optimize the conditions at which IPTG is utilized to stimulate the expression of recombinant IL-18BP isoform A depending on the particular application. It would be routine for one to arrive at the expression conditions for the application they intend on using the recombinant IL-18BP isoform A. Therefore, the above invention would have been prima facie obvious.
However, Lee does not teach the method of claim 1 of connecting a 5’ end of a coding gene of the recombinant IL-18BP with a gene sequence of a molecular chaperone Sumo to construct a fusion gene, inserting the fusion gene into a cell expression vector (claim 1) and SEQ ID NO: 1, 2, 3 (claim 1). The method of claim 2, wherein the cell expression vector comprises pET-20b(+) (claim 2).
With respect to claims 1-2, Zhang teaches a method wherein a pET-20b-SUMO-protein plasmid was created as a fusion construct to acquire high-level production, soluble expression, and bifunctional activity (page 5499, column 2, para 1). Since the (+) in pET-20b(+) is an indication that the vector is in the correct reading frame, Examiner is interpreting the pET-20b vector taught by Zhang to be pET-20b(+) as Zhang teaches the subsequent expression of the SUMO-protein fusion (page 5501, column 1, para 1), which is an indication that said vector is within the correct reading frame. Absent evidence otherwise, it is the Examiner’s opinion that the SUMO protein (SEQ ID NO: 2) taught by the instant application is the same SUMO protein taught by Zhang as the SUMO protein taught by Zhang has the same activity of the SUMO protein recited in claim 1 of a small ubiquitin modifier (abstract). A 5’ end of a coding protein was connected to the SUMO protein and inserted into the pET-20(b) vector (page 5500, column 2, para 2).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to apply the teachings of Lee et al. of a method of producing a recombinant IL-18BP isoform A cloned within a pLysE vector and transformed within an E. coli host cell and cultured in LB broth (page 518, column 1, para 3, 4) or combined the teachings of Zhang et al because Zhang teaches a method wherein a pET-20b-SUMO-protein plasmid was created as a fusion construct to acquire high-level production, soluble expression, and bifunctional protein activity (page 5499, column 2, para 1).
One of ordinary skill in the art would be motivated to either use the teachings of Lee by itself or combine the teachings of Zhang because Zhang provides the motivation for Lee to fuse a SUMO molecular chaperone to recombinant IL-18BP as the SUMO molecular chaperone would allow for high-level production, soluble expression and bifunctional activity of IL-18BP (Zhang, page 5499, column 2, para 1). Furthermore, Lee would be motivated to utilize the pET-20b vector taught by Zhang as Zhang teaches said vector is IPTG inducible, as claimed by Application in claim 1 of the instant Application, (page 5501, column 1, para 1) and can successfully express protein fused with SUMO (page 5501, column 1, para 1). One would be motivated to make the recombinant IL-18BP fusion using the human immunoglobin class G-crystallizable fragment (IgG-Fc) (instant application SEQ ID NOs: 1, 3) for the treatment of IL-18 immune diseases in humans since IL-18BP has very high affinity to IL-18 and neutralizes its activity (Zhang: page 517, column 2, para 4 and page 518, column 1, para 1). In addition, fusing IgG-Fc to hIL-18BP would allow for the recombinant IL-18BP to be easily purified via affinity column chromatography (Lee: page 517, column 2, para 4 and page 518, column 1, para 1). One would be motivated to add SUMO to said fusion gene as SUMO is well-known in the art to aid in the expression of protein at which it is fused. Supporting the Examiner’s position is the evidentiary reference of Butt, which recites SUMO enhances the expression and solubility of protein (page 4, column 2, para 1). As such, absent evidence otherwise, it is the Examiner’s opinion that fusing SUMO (instant application SEQ ID NO: 2) to the recombinant hIL-18BP (SEQ ID NOs: 1 and 3) would be obvious to one of ordinary skill in the art as said regulatory protein is well-known in the art to enhance the expression and solubility of protein for purification (Zhang: page 5499, column 2, para 1). Thereby, it is not inventive to add SUMO to recombinant hIL-18BP. One of ordinary skill in the art knowing the benefit of fusing IgG and SUMO to IL-18BP to enhance expression and purification would have a reasonable expectation of success that a fusion protein comprised of IL-18BP-IgG (instant application SEQ ID NO: 1) and SUMO (instant application SEQ ID NO: 3) could be utilized for a method of fermenting and producing recombinant IL-18BP since Lee teaches the expression and purification of IL-18BP from a plasmid under IPTG inducing conditions (page 518, column 1, para 3) and Zhang teaches the utilization of SUMO within pET-20(b) (Zhang: page 5500, column 2, para 1) for the purification of protein and its usefulness in increasing the yield of protein for purification purposes (Zhang, page 5505, column 2, para 1).
One of skill in the art would have a reasonable expectation of success to make and use the claimed fusion protein because Lee teaches a method of producing a recombinant IL-18BP isoform A cloned within a pLysE vector and transformed within an E. coli host cell and cultured in LB broth (page 518, column 1, para 3, 4). Whereas, Zhang teaches a method wherein a pET-20b-SUMO-protein plasmid was created as a fusion construct to acquire high-level production, soluble expression, and bifunctional activity (page 5499, column 2, para 1). Therefore there would be a reasonable expectation of success to arrive at the above invention. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
Status of the claims
Claims 1-2 are pending
Claims 1-2 are rejected
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERICA NICOLE JONES-FOSTER whose telephone number is (571)270-0360. The examiner can normally be reached mf 7:30a - 4:30p.
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/ERICA NICOLE JONES-FOSTER/ Examiner, Art Unit 1656
/MANJUNATH N RAO/ Supervisory Patent Examiner, Art Unit 1656