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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-9 and species: leucine at position 393 in the reply filed 12/21/2023 is acknowledged.
Claims 4, 10-17 are withdrawn from consideration pursuant to 37 CFR1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 12/21/2023.
Claims 1-2 and 6-9 are now under consideration in the instant Office Action.
Withdrawn Rejections
Rejections of claims 8-9 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paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter are hereby withdrawn in view of amendments to the claims.
Rejections of claims 1-2 and 8-9 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claim upon which it depends, or for failing to include all the limitations of the claim upon which it depend re hereby withdrawn in view of amendments to the claims.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, and 8-9 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.
See MPEP §2163(I)(A) which states: "The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. 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.”
Claims 1 and 8-9 call for a luciferase mutant with a functional requirement improving thermostability. There is no specific structural requirement for the full identity of the luciferase mutant variant beyond the required function. The claims recite the amino acid sequences for the luciferase mutants with the terminology “an amino acid sequence”. There is no limitation or exclusion in the claim language that recites which parts of the amino acid sequences remain unaffected by modifications due to the claim language of “an amino acid sequence”, which widens the scope of the claim to encompass an immense number of unknown molecules that share some percentage identity to the claimed sequences and can perform the claimed function. Applicant has not demonstrated that they are in possession of all the molecules that fall within the immense scope of the claim that are able to achieve the claimed function.
The use of “an amino acid sequence” can be interpreted as comprising the whole sequence or only comprising some of the amino acids contained within the sequence. As currently recited, the language of “an amino acid sequence” reads on less than the amino acids listed in the sequence identity number that are capable of binding to any isolated antigen. Dependent claims 8 and 9 recite percent identities of 95-98%, but this leaves anywhere from 2-5% of the amino acid sequence undefined. Given the large length of the sequences, this would allow for substantial amounts of substitution from the original base sequence, and Applicant has not provided sufficient description of all the possible combinations that could arise and still be encompassed by the broad claim language. There is a lack of support for all of the potential amino acid sequences that are possible as claimed that are capable of improving thermostability. Applicant is encouraged to amend the claim language to “… comprising the amino acid sequence of SEQ ID NO: … ” in the instant claims to obviate this rejection.
There are a few specific examples of luciferase mutants in the instant specification, but there is no support provided that the Applicants have envisioned all of the possible variants encompasses by these functional requirements of the instant claims. The language of the claims which recite “an amino acid” is so broad and reads on so many possible mutated sequences that the instant specification fails to describe any or all of the possible mutants that are encompassed by this term. The term “luciferase mutant” described by unbound amino acid sequences encompasses many potential sequences encompassing undefined modifications so long as they achieve the required function of improved thermostability. Thus, the claims are drawn to genera of molecules that are defined only by their function. Therefore, the genus is merely defined by function and the instant specification fails to describe the full genus of molecules that are encompassed by this claim.
To provide adequate written description and evidence of possession of claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of prospective activity or function. There is not even identification of any particular portion of the structure that must be conserved for said activity except its function. The specification does not provide a complete structure of all possible forms of the claims agents and variants and fails to provide a representative number of species for any genera. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genera of luciferase mutant variants.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that they invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed structure of the encompassed agents, fragments and variants, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Modified Rejections Necessitated by Amendment
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.
Claim(s) 1-2 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Dementieva et al. 1996 (in IDS filed 01/04/2021), in view of Kikkoman (EP0524448 A1, in PTO-892 filed 03/27/2024).
Dementieva et al. teaches the physico-chemical properties of the recombinant L. mingrelica luciferase synthesized by E. coli cells, which is 548 amino acids in length and is an 81% identity match for instant SEQ ID NO: 1. The catalytic and spectral properties of recombinant luciferase were “similar to those of the native enzyme but the former was less stable in the presence of the additional Cys[teine] residue. The mutant forms of L. mingrelica firefly luciferase with point mutations … , Cys-393-->Ala … , have been constructed using the method of site-specific mutagenesis… The Cys-393-->Ala mutant appeared to be more stable in comparison with the native enzyme”, see Abstract. Dementieva et al. further states that a variant wherein cysteine 393 was replaced by alanine exhibited slower thermal denaturation and improved stability when compared with the wild type, see Table 1.
In regards to instant claims 1-2 and 6, it would have been prima facie obvious to one of ordinary skill in the art to select leucine for the amino acid substitutions as it is a nonpolar amino acid with structural, chemical, and functional similarities to alanine; such would amount to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; which is proper to support a finding of obviousness under 35 U.S.C. 103(a). See the Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396). See also MPEP §2143(E).
One skilled in the art would recognize that the amino acid list recited by Applicant in the instant claims comprise either conservative amino acid substitutions which result in the replacement of one amino acid by another that is chemically similar, or nonconservative amino acid substitutions whose replacement does not negatively affect binding and the overall function of the protein. Thus, it would be reasonable to expect that substituting either alanine, leucine, or another similar amino acid that confers similar properties at position 393 would improve thermostability of the luciferase protein. This meets the limitations of instant claim 1 wherein a luciferase mutant contains a non-polar amino acid substitution at position 393 of SEQ ID NO: 1 and instant claims 2 and 6 wherein the amino acid substitution comes from the nonpolar amino acids such as leucine, proline, valine, or isoleucine.
Dementieva remains silent on the amino acid mutation at position 217. Kikkoman remedies this deficiency.
Kikkoman teaches SEQ ID NO: 8, which comprises a thermostable mutant luciferase of a firefly, in which an amino acid at position 217 of the luciferase of Luciola cruciata (GENJI firefly) of Luciola lateralis (HEIKE firefly) is replaced by a hydrophobic amino acids, for examples isoleucine, leucine, or valine, see reference’s claims 10-12. The mutant luciferase is identical in properties to the wild-type luciferase except that it is stable when heated to high temps., e.g. 50 degrees C. SEQ ID NO: 8 taught by Kikkoman is a 100% match to instant SEQ ID NO: 1. This meets the limitations of instant claim 7 wherein the luciferase mutant comprises an amino acid substitution of leucine at position 217 of SEQ ID NO: 1, and instant claims 8 and 9 wherein the mutant luciferase is a 100% sequence identity match to SEQ ID NO: 1.
It would be obvious at the time of the instant invention to use the nonpolar amino acid substitutions at position 393 of SEQ ID NO: 1 taught by Dementieva, which is a substitution that results in improved thermal stability of the protein, with the modifications taught by Kikkoman which confer additional thermostable properties as well as sequence identity matches to the protein. One would be motivated to combine the amino acid substitutions at position 393 with the amino acid substitutions at position 217 on SEQ ID NO: 1 with the expectation of creating a mutant luciferase protein with improved thermal stability and minor chemical or structural changes from the amino acid substitutions at position 393.
Therefore, claims 1-2, 6-9 are rejected as obvious over Dementieva and Kikkoman.
Response to Arguments
Applicant's arguments filed 01/14//2026 have been fully considered but they are not persuasive.
Applicant argues the Examiner “start[ed] from the amino acid list recited by Applicant in the instant claims and recognizing that they comprise conservative amino acid substitutions is a logic based on hindsight knowledge of the results in Table 2 of the present specification.” This is not found persuasive.
According to Table 2 of the instant specification, it appears that Applicants have simply substituted all twenty standard amino acids into position 393 and tested for relative thermostability. Applicant uses the native sequence’s cysteine at position 393 as a baseline, and reported a “residual activity ratio after 90 minutes” of 1.00. When substituting amino acids aspartic acid and glutamic acid, Applicant received scores of <1.00, which reflects the lack of similarity of structure of these amino acids and how it impacts the overall thermostability of the molecule. When substituting the remaining 17 amino acids, Applicant received varying values greater than 1.00, ranging from 1.02 for arginine to 1.65 for leucine. The substitution of alanine at position 393 resulted in an increase in activity valuing 1.43, which signifies improved thermostability.
As is discussed, this method of substituting all known options and measuring for “effectiveness” in certain conditions is considered routine and standard in the art. It would not require undue experimentation for one of ordinary skill in the art to test for all amino acid substitution combinations, while also recognizing that certain conservation substitutions are more likely to confer advantageous properties and thus would be favorable to substitute. The list of potentially substitutable amino acids starts at 20, but can be narrowed to fewer when selecting for a particular quality such as thermostability. This results in a far smaller list of potential amino acids to substitute, at which point one of ordinary skill in the art would be able to test based on what was known at the time of filing. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007).
In regards to the values obtained for “residual activity ratio after 90 minutes”, there is no analysis of what these values represent aside from a baseline of 1.0, which represents a maintenance in activity. As such, one would not be able to infer from the data what an unexpected result would be, or if a certain effect was more pronounced. The table represents raw values obtained from experimentation and do not provide context for what would be considered a marked improvement. For example, it is unclear if the difference between the values for phenylalanine at 1.35 and alanine at 1.43 is more drastic when comparing alanine at 1.43 to methionine at 1.50. Since all of the values on the chart remain close in value, excluding glutamic acid and aspartic acid, the chart alone does not convey the significance of substituting one amino acid over the other. Applicant fails to provide sufficient context for the data as the basis of arguing that some values are unexpected over others.
Applicant argues “the skilled person in the art at the time of filing … would not have expected that substituting one amino acid with another similar amino acid that confers similar properties would improve thermostability of the protein.” This is not found persuasive.
As discussed above, Applicant substituted all known amino acids at position 393 of SEQ ID NO: 1. From this, they reported values of residual activity ratios and found that with the exclusion of two amino acids, all substitutions reported back either no change in activity or a slight increase in activity. As discussed in the prior art, one of ordinary skill in the art recognizes that certain amino acids, such as alanine in Dementieva et al., would be a favorable substitution for the purposes of thermostability. Dementieva et al. teaches the substitution of cysteine from the wild type native sequence to alanine in the mutated sequence as such changes would confer slower thermal denaturation and improved stability when compared with the wild type. One of ordinary skill in the art would recognize that when trying to optimize certain properties in a protein, conservative amino acid substitutions are viable options in exploring optimal characteristics. At the time of filing, the disclosure of Dementieva et al. recognizes that the substitution of the amino acid at position 393 is a method to stabilize the luciferase mutant enzymes and pursues this avenue by substituting alanine for cysteine. This finding is reflected in Table 2, where the substitution of alanine observed an increase in residual activity. As such, the prior art provided the reasoning for substituting particular amino acids and the instant specification repeats these findings.
Applicant argues “even if it is assumed arguendo that optimizing a particular property in a protein with amino acid substitutions is considered routine and conventional within the art, this does not mean the skilled artisan can predict or expect what characteristics would be provided by substituting position 393 of SEQ ID NO: 1 with leucine, proline, valine, isoleucine, histidine, or methionine.” This is not found persuasive.
Given that both the instant claims list amino acids such as leucine, valine, and isoleucine as potential substitutions for position 393 and the prior art considers these types of substitutions for luciferase mutants beneficial at this particular position, it would be considered obvious to try and select amino acids substitutions that would confer similar or more advantageous properties. It is not a condition for obviousness or routine experimentation to predict exactly which substitutions would have the “most” advantageous outcomes prior to experimentation; however, one of ordinary skill in the art would be able to narrow down a selection of amino acids that may be advantageous and perform experimentation to ascertain which would be best from a larger list. A degree of predictability that one of ordinary skill would have found to be reasonable to perform said substitutions is sufficient.
It would have been prima facie obvious to one of ordinary skill in the art to choose certain amino acids for substitution from a list of finite amino acids; such would amount to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; which is proper to support a finding of obviousness under 35 U.S.C. 103(a). See the Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at <http://www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf>). See also MPEP §2143(E).
See KSR, 127 S. Ct. at 1740. "When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product is not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show it was obvious under 35 U .S.C. 103." KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1742, 82USPQ2d 1385, 1396 (2007). This predictability of which amino acids are best to substitute allow one of ordinary skill in the art to expect success, without the need for predicting exactly what outcomes or characteristics they expect to receive prior to conducting experimentation.
It would have been obvious to the ordinary artisan to modify the luciferase mutant to improve thermostability because it was already known that such changes could be advantageous due to the nature of luciferase in tracking ATP activity at higher temperatures. While the exact parameters of how “successful” each modification would be to the protein do not need to be determined at the outset of experimentation, the teachings of the prior art by the filing date would provide guidance into selecting from the broader genera a smaller class of amino acids which have been known to produce similar or better results. Conducting experimentation to modify the protein to reach this endpoint is a part of routine optimization.
Therefore, the rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675