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 .
Claim Status
Claims 1 and 4-9 are currently pending in this US patent application and were examined on their merits.
Information Disclosure Statement
The information disclosure statement filed in this application on 05/06/2023 has been received and considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 4-9 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.
Claim 1 recites a mutant enzyme comprising a glycine and histidine ligase with mutations “on sites T244I, S290L, G292W, E84K, A158H, and G159D of a wild-type L-amino acid ligase Lal” and a tripeptide ligase with mutations recited in an analogous fashion. A wild-type amino acid ligase would not have “sites T244I, S290L, G292W, E84K, A158H, and G159D,” as it would not have mutated residues present at any location in the protein by the definition of the term “wild-type.” As such, one of ordinary skill in the art would be unable to determine the metes and bounds of the GHS enzyme or the HKS enzyme recited in instant claim 1, rendering it indefinite.
Because claims 4-9 incorporate all limitations of the indefinite claim 1 and do not provide further limitation of the indefinite language therein, these claims are also indefinite. Therefore, claims 1 and 4-9 are rejected under 35 U.S.C. 112(b).
In the interest of compact prosecution, the Examiner has interpreted the limitation “mutations on sites T244I, S290L, G292W, E84K, A158H, and G159D of a wild-type L-amino acid ligase Lal” to indicate that the GHS enzyme is an L-amino acid ligase enzyme with the following mutations as compared to the sequence of a wild-type L-amino acid ligase: T244I, S290L, G292W, E84K, A158H, and G159D. The Examiner has interpreted the limitation “mutations on sites V150F, S153E, E228I, N230H, D233T, R285V, D130Q, E146L, N148S, G387N, and I445D of a wild-type glutathione synthase gshB” to indicate that the HKS enzyme is a glutathione synthase enzyme with the following mutations as compared to the sequence of a wild-type glutathione synthase gshB: V150F, S153E, E228I, N230H, D233T, R285V, D130Q, E146L, N148S, G387N, and I445D.
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 4-9 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 particular mutant enzymes comprising GHS and HKS and for methods of using those particular enzymes to produce the tripeptide prezatide, does not reasonably provide enablement for any enzyme comprising the recited mutations or for the use of any enzyme comprising the recited mutations to produce prezatide. 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 or practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
As discussed above, the claims are drawn to (claim 1) a mutant enzyme comprising particular mutations at particular sites “of a wild-type L-amino acid ligase Lal” and of a method of producing prezatide using any enzyme of claim 1. The instant claims are drafted using open-ended “comprising” language, thus allowing the GHS enzyme of claim 1 to contain any additional mutations with respect to a wild-type amino acid ligase along with the specifically recited mutations, nor do the claims specify which L-amino acid ligase is to serve as the wild-type enzyme from which the mutant GHS is developed. The claims also do not require the enzyme of claim 1 to contain any particular enzymatic activity. Thus, the claims taken together with the specification imply that any wild-type L-amino acid ligase Lal can comprise the six specific mutations recited in instant claim 1 and that any such enzyme can be used to synthesize prezatide as recited in instant claim 4 and its dependents, including enzymes with any number of additional mutations.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
Wang (Wang et al., Enzyme and Microbial Technology 136: 109537 (2020; published online 02/26/2020)) teaches that several L-amino acid ligases (Lals) were known at the time of Applicant’s filing (several months following the publication of Wang). The prior art gives no indication that amino acid ligases other than the particular one given in instant SEQ ID NO.: 1 would have amino acids T244, S290, G292, E84, A158, or G159. Wang also teaches that different Lal enzymes have different substrate specificities (see, for example, under headings 2.1-2.7).
As such, the state of the prior art at the time of Applicant’s invention as demonstrated by Wang indicates that the presence of the particular recited amino acids in any Lal enzyme or the use of variants of any Lal enzyme to synthesize Gly-His was highly unpredictable, as was the use of Lal enzymes with any additional mutations other than those recited in instant claim 1.
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The instant specification discloses two particular mutant enzymes, GHKS-1 and GHKS-2, which contain the recited mutations but do not contain any other variations from the sequence of the particular wild-type Lal enzyme from which they were derived. These enzymes were shown to have prezatide synthesis activity. The instant specification provides no examples of prezatide synthesis occurring in the presence of any other mutated sites in GHS enzyme with respect to the wild-type Lal or any guidance about how one of ordinary skill in the art may be able to construct such an enzyme (see instant specification, Table 1).
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by Wang, the high unpredictability, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to either make the mutant enzyme of claim 1 from any Lal enzyme or to use any enzyme that falls within the broad scope of claim 1 to synthesize prezatide.
It is the Examiner’s position that one skilled in the art could not practice the invention commensurate in the scope of the claims without undue experimentation. It is also noted, considering the a priori unpredictability in the art with regard to Lal enzymes and prezatide synthesis, that, while the specific enzymes GHKS-1 and GHKS-2 and their use to synthesize prezatide are enabled, the full scope of claims 1 and 4-9 is not enabled.
Claims Are Free of the Prior Art
The closest prior art to the claimed invention is found in the teachings of Wang, who discusses L-amino acid ligase enzymes and their substrate specificities (see above for citation). However, Wang does not teach or suggest making the particular mutations recited in instant claim 1 in any of the Lal enzymes, nor does Wang teach or suggest fusing such a Lal enzyme with a glutathione synthase having the mutations recited in instant claim 1 or using such a fusion enzyme to synthesize prezatide as recited in instant claim 4. As such, the instant claims are free of the prior art.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Erin M. Bowers, whose telephone number is (571)272-2897. The examiner can normally be reached Monday-Friday, 7:30-5:00.
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/Erin M. Bowers/Primary Examiner, Art Unit 1653 01/29/2026