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 .
Priority
This application is a National-Stage entry of PCT/EP2022/056188, filed 3/10/2022. Applicant’s claim for the benefit of a prior-filed application EP21162531.4, filed 3/15/2021, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/23/2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant's election with traverse of Group I (originally, claims 1-11 and 16-20) in the reply filed on 12/11/2025 is acknowledged. Applicant’s election of the species comprising an enzyme variant with T65I or T65V and at least two of the substitutions of N61D, S82R, K107Q, T127V, T127S, G149N, S164D, and L181S* (in the remarks it is written “L182S” but it is clear this is a typo for “L181S”, as in the claims and the original disclosure). The traversal is on the grounds that there would not have been a serious burden on the examiner if all of the species were examined in a single application. This is not found persuasive because, as set forth in the Restriction Requirement rejection mailed 11/21/2025, the restriction among the different groups and the requirement for an election of species is based upon the lack of any shared special technical features- when considered over the knowledge in the prior art- in this National Stage (371) entry of international application PCT/EP2022/056188. Regarding the applicant’s argument that there would not have been a serious burden on the examiner if all of the species were examined, this argument is not persuasive because each of the distinct species set forth in the election of species requirement would have required its own search query, with particular sequence searching as well as text and keyword searching for the different combinations of mutations. When considering at least two substitutions, there are about 36 different combinations for each of the options a) - g) (in the claims filed 8/23/2023), but because there could be greater than two substitutions, the actual number of combinations to consider is much higher. Because of the considerable time and resources required for the complete search, there is deemed to be serious burden on the Examiner.
The requirement is still deemed proper and is therefore made FINAL.
Response to Amendment
Applicant’s remarks and amendments filed 12/11/2025 are acknowledged and have been fully considered.
Applicant’s amendment to the claims is acknowledged. This listing of the claims replaces all prior versions and listings of the claims. Claims 1-20 were canceled in the amendment. Newly added claims 21-32, directed to the elected invention, are pending and have been examined on the merits.
Specification
TITLE OF THE INVENTION:
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The titled as filed only recites “Polypeptide Variants”. At a minimum, the title should be amended to indicate that the polypeptides comprise DNases, which is crucial to the invention.
The following title is suggested: “Polypeptide Variants Having DNase Activity”
ABSTRACT OF THE INVENTION:
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because the abstract does not describe what is new in the art to which the invention pertains, nor does the abstract describe any particular improvements, preferred modifications, or specific embodiments. It is suggested that the abstract be updated to include the amended claim’s subject matter. The abstract should recite the substitutions that are critical to the claimed DNases (e.g. T65I/V and two or more mutations selected from N61D, S82R, K107Q, T127S/V, G149N, S164D, and/or L181S).
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The specification is objected to because of the following informalities:
TRADE NAMES, TRADEMARKS, AND OTHER MARKS USED IN COMMERCE:
The use of the terms Tween® 20 (pg. 56) and Triton® X-100 (pg. 58); which are each a trade name or a mark used in commerce, has been noted in this application. The term(s) should be accompanied by the generic terminology; furthermore the term(s) should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term(s).
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks (see MPEP 608.01(v) and 608.01(u)).
Appropriate correction is required.
Claim Objections
Claim 21, 28, and 29 are objected to because of the following informalities:
In claim 21, line 7, it is recommended to amend the term “T127S/V” to “T127S or T127V”. This is for improved clarity, and to conform with the style used for similar mutually exclusive mutations in the other claims (e.g. “Q14R or Q14W” in claim 27, line 3, et cetera).
In claim 28, line 18, the word “and” is used, and is unnecessary in separating the list of alternatives, which ends in “; and”, prior to the last option.
In claim 29, line 4, the word “and” is used, and is unnecessary in separating the list of alternatives, which ends in “; and” (line 9).
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.
Claims 21-32 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 21 recites a number of potential mutations of the DNase variant, referred to by a position on a reference sequence. However, although the claim recites “the variant has at least 60% sequence identity to SEQ ID NO: 1”, the claim does not recite what reference sequence from which the position of the substitutions is to be determined by comparison. No specific parent variant is required in Claim 21 as a reference point. Further, there is a great amount of variation in polypeptides having at least 60% sequence identity, as up to 40% of the polypeptide may be different. The determination of the correct positions of the claimed substitutions may be difficult if not impossible in heavily divergent but still 60% similar proteins. The resulting claims are therefore indefinite as there is no claim limitations that identify the positions of the substitutions by reference to a defined sequence (e.g. to SEQ ID NO:1). Although claims are interpreted in light of the specification, limitations are not imported from the specification and claim language is afforded the broadest reasonable interpretation (B.R.I.) during examination.
For the sake of compact prosecution and comparing to the prior art, the claim has been interpreted under the B.R.I. in light of the specification as reciting “wherein the variant comprises three or more amino acid substitution(s) compared to SEQ ID NO:1” or “wherein the positions correspond to the positions of SEQ ID NO: 1”. See U.S. Patent Nos. 10,781,408 and 10,774,293 for exemplary language clarifying the amino acid substitutions by reference.
Claim 21 recites, in lines 8-9:
“T127S/V,
G149N or S164D, and
L181S; ”
which ends a list of potential substitutions. The resulting claim encompasses a variant DNase comprising three substitutions, one of which must be T65I or T65V, and at least two others chosen from the recited list. However, one cannot determine if the recitation of “G149N or S164D” refers to mutually exclusive substitutions or merely two separate alternatives. In other words, there is no way to determine if a DNase variant that comprises T65V, G149N, and S164D falls within the scope of patent protection which is desired. This is further complicated by the inclusion in a list of alternatives (a Markush-type claim) and the spacing of the lines in the claim. This element recites separate residues (e.g. that of G149 and S164 according to SEQ ID NO: 1) and does not include clearly mutually exclusive substitutions (e.g. “T65I or T65V”). Further, the dependent claim 28 and the specification recites that the set of substitutions can include, inter alia, the combination of “Q14W+N61D+T65I+R109T+G149N+S164D+L181W”.
The resulting claim does not clearly set forth the metes and bounds of the patent protection desired and one would not reasonably be apprised of the claimed scope. Thus, the claim language is indefinite. Correction is required. A suggestion to overcome this indefinite scope is to eliminate the word “or” and place “G149” and “S164” onto separate lines.
All other claims depend directly or indirectly from the rejected claims and are, therefore, also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the reasons set forth above.
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.
Claims 21-25 and 27-32 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 claims 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.
Claim 21 recites a DNase variant which comprises: (i) T651 or T65V; and (ii) at least two substitutions selected from the group consisting of N61D, S82R, K107Q, T127S/V, G149N or S164D, and L181S; (iii) wherein the variant has at least 60% sequence identity to SEQ ID NO: 1 and (iv) has DNase activity. Claims 22-26 limit this sequence identity to 70%, 80%, 85%, 90%, and 95%, respectively.
The claims thus encompass any and all DNase variants that have the i) T651 or T65V; and (ii) at least two substitutions of N61D, S82R, K107Q, T127S/V, G149N, S164D, and L181 and DNase activity, while having the claimed minimum identity in the unspecified residues.
SEQ ID NO: 1 recites a sequence of 182 amino acids. If 60% of the residues are identical then a variant according to the instant invention can have up to 40% variance. This amounts to ~72 positions, at least three of which must be the indicated mutations of (i) and (ii) as described above. The remaining 69 amino acids are permissive of any other amino acid (e.g. 19 different ones from the wild-type). This amounts to at least 1.71x1088 possible variants (69 positions with 19 possible variants is 1969). For claim 22 there are ~1.65x1065 possibilities (1951), claim 23 contains 1.58 x1042 (1933), claim 24 contains 4.9x1030 (1924), claim 25 contains 1.52x1019 (1915) possible variants, and claim 26 has 4.7 x 107 (196) variants.
According to the B.R.I. of the claim, when viewed in light of the specification, there exists a nearly limitless number of sequences within the claimed scope (trillions of trillions for claims 22-24). Comparatively, the specification only recites a small number of species of the broad genus that meets the recited limitations, including maintaining DNase activity.
MPEP § 2163.(II)(A)(3)(a) states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The specification states, generally, that the DNase activity may be defined by the presence of one of the motifs [D/M/L][S/T]GYSR[D/N] (SEQ ID NO: 25) or ASXNRSKG (SEQ ID NO: 26) (see page 21), however this is not required in any of the examined claims, nor is it sufficient to account for the vast amount of variant allowed in the recited claims (trillions of variants). The specification describes algorithms used to predict protein homology by sequence identity (pages 8-9), however this amounts to a description of determining sequence homology and not any specific algorithms for predicting protein stability and/or enzyme activity.
The specification fails to reasonably describe the full genus of the claimed invention by providing identifying characteristics or functional properties of the sequences which can predictably lead to an understanding of whether there will be DNase activity, and if the variant will have putative improved characteristics disclosed in the specification, such as improved stability. The instant specification does not disclose identifying characteristics, such as key structural or other physical properties, or functional characteristics coupled with a known or disclosed correlation between function and structure, such that the entirety of the claimed genus is encompassed by the description in the disclosure.
Regarding the level of knowledge in the art around the time of the applicant’s invention and pertaining to problems regarding prediction of mutational effects and protein stability changes, Fang ("A critical review of five machine learning-based algorithms for predicting protein stability changes upon mutation", Briefings in Bioinformatics, Volume 21, Issue 4, July 2020, Pages 1285–1292) teaches that although machine learning (ML)-based algorithms have been proposed for predicting mutation-induced stability changes in proteins, all of them suffer from the problem of overfitting (Abstract, Table 2, Figure 3). Further, Fang teaches the ML approaches are not as robust as claimed and that “in a blind prospective validation, none of 63 mutants predicted to be stabilizing were experimentally observed to be stabilizing” (pg. 1286, left col, 2nd paragraph). Fang concludes after vigorous testing that “these newer algorithms still suffer from the problem of overfitting and show no improvement over the older methods” (pg. 1286, left col, 4th paragraph) and “For a problem as complex as predicting stability changes upon mutation, one should never have expected good performance based on rudimentary features such as residue composition, etc.” (pg. 1290, left col, last paragraph). Indeed, from this recent perspective, even applying advanced algorithms involving Machine Learning, one would cannot predict stability effects of protein mutations, from among trillions of possible variants, based only on sequence homology, as described in the Applicant’s disclosure herein (see e.g. the description of algorithms on pages 8-9). Further, Fang teaches that these algorithms require more data than solely the sequence of a protein and the identity of substituted residues (Table 1, page 1289, right col, under “Types of features relevant to protein stability changes”).
The specification, in view of the art cited above, does not describe a manner in which one can use a sequence, i.e. the structure, and reliably predict the effectiveness of any and all claimed variants on the activity and/or structure of the DNase. In other words there is no known or disclosed correlation between function and structure that amounts to a sufficient description of the entire claimed genus.
The examples in the specification include the combinations in Table 1A, Table 1B, Table 2, and Table 3. This appears to be around in the order of magnitude of 100-200 disclosed combinations. Further, the combinations of mutations in the examples only include those specified residues, at the specific residues and substitutions required in the claims. This fails to account for the other residues, and the up to 60% variations allowed therein (i.e. with any of the 20 available amino acids).
Thus, the specification only provides only a relatively small number of specific examples of the claimed genus, which cannot be considered a sufficient description of a representative number of species by actual reduction to practice of the full breadth of the vast genus, comprising more than trillions of variants in the case of claims 21-25.
There is no evidence on the record that, at the time of filing, the Applicant possessed additional representative species of the full genus recited in the claims beyond those provided in the working examples.
For these reasons, the disclosure fails to provide adequate written description to support the entirety of the broad genus claim to any and all variants having at least three of the claimed substitutions and having DNase activity.
Claim 26 are further limited to variants having at least 95% identity, which amounts to 19^6 or 4.7x10^7 possible polypeptides. This is a large amount, but using high throughput assay methods, in view of the teachings in the specification and the high level of knowledge in the art, screening through these to determine those which have DNase activity and meet the claim limitations is feasible. Further, the instant disclosure has examples and embodiments having up to 8 amino acid substitutions (compared to SEQ ID NO:1) which have activity and have increased stability (see the variant having the combination of N61D, T65I, S82R, T127S, S164D, T171E, D175G, and L181S in Table 2). Thus there is sufficient description of the invention for the DNase variants of claim 26.
Claims 21-25 are rejected under 35 U.S.C. § 112(a) because the claimed subject matter is not described in the specification in such a way as to reasonably convey to a skilled artisan that the inventor or joint inventors had possession of the claimed invention.
The dependent claims 27-32 are also rejected under 35 U.S.C. § 112(a), because these claims require the DNase variant of claim 1, and fail to practically further limit the claimed invention to a reasonable degree of similarity to that of the disclosed embodiments.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 21-24, 27-30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Beier et al. (US PGPub 20190256831, published 8/22/2019, later issued as US Patent No. 10,774,293).
Beier et al. (US 20190256831) teaches a variant of a DNase parent, derived from Bacillus Cibi, wherein the variant has at least 80% sequence identity to the polypeptide shown in SEQ ID NO: 1 and the variant has DNase activity, wherein the variant comprises one or both motifs [D/M/L][S/T]GYSR[D/N] (SEQ ID NO: 25) or ASXNRSKG (SEQ ID NO: 26) (as also disclosed in page 21, lines 23-33 of the instant application), wherein the variant comprises one or more substitutions compared to SEQ ID NO: 1, and wherein the substitutions comprise, inter alia, T65I, T65V, N61D, S82R, K107Q, and/or T127V (claim 1, Abstract, and [0092]-[0094]).
Beier teaches that “Each of these mutations provides at least one improved property, such as improved stability, when introduced in SEQ ID NO: 1 or polypeptides having at least 60% sequence identity hereto. It will be clear to the skilled artisan that each of these mutations provides an improved effect thus 2, 3, 4 etc. of the above substitutions may increase this effect. Thus some aspects of the invention relate to DNase variants comprising at least two, three, four, five, six, seven, eight of the substitutions” ([0125]). The substitutions to be selected from comprise N61D, T65I, T65V, S82R, K107Q, T127S and T127V ([0125]), as recited in the instant claims. In Table 1 (see pages 42-45 therein), Beier teaches that these mutations impart improvements to the stability, indicated by a “half-life improvement factor”. Of note, Beier teaches that T65I = a HIF of 1.14; T65V = 1.10; N61D = 1.09; S82R= 1.10; K107Q = 1.14; T127S = 1.20; and T127V= 1.38.
SEQ ID NO:1 of Beier is about 87.4 percent identical to the variant SEQ ID NO:1 of the instant invention (see the alignment in Appendix A, included at the end of this action). It is noted that SEQ ID NO:27 of the instant application, reciting the parent DNase, from Bacillus cibi, is identical to SEQ ID NO:1 of Beier. The aligned sequences are of the same length and the substitutions made thereto are of the same comparative positions as in the instant invention.
Further, regarding the additional substitutions recited in dependent claims 27-29, Beier teaches the substitutions may include, inter alia, Q14R, the variant S25P (note that the instant claim requires a serine at position 25 in “P25S”, Beier teaches a sequence that has serine and may be mutated to proline), D56I, D56L, S68L, T77Y (e.g. Y77), Q109R (e.g. Q109), S116D (e.g. S116), and S181W (thus a variant with W181) ([0125]).
Regarding claim 30, it is noted that many of the possible specified residues pertain to the original sequence of the instant SEQ ID NO:1, in other words the limitations are reciting that these positions are the original and are not mutated. Beier teaches at least the following mutations, made to the original parental sequence (the same as SEQ ID NO:27 herein): T1I, S13Y, T22P, S25P, S27L, S39P, S42G, S57W, S59V, V76L, T77Y, Q109R, S116D, S144P, A147H, S167L, G175D ([0125]), thus teaching at least 5 (Beier teaches “variants comprising at least two, three, four, five, six, seven, eight of the substitutions”, [0125]).
Therefore, prior to the effective filing date of the instant invention, to one of ordinary skill in the art, the instantly claimed DNase variant would have been prima facie obvious over the teachings of Beier, which teaches a variant having 87.4 identity to the claimed SEQ ID NO:1 and having at least two, three, four, five, six, seven, eight of the substitutions taught therein, including T65I or T65V, N61D, S82R, K107Q, and/or T127V as the instant claim 21.
One would have been motivated by Beier to produce a DNase variant from the same starting parental DNase as the instantly claimed mutant by combining the substitutions taught therein. The substitutions taught in Beier are beneficial because of the improved stability on the DNase polypeptide. These substitutions would predictably convey the same properties to the instantly claimed sequence. Thus, one having ordinary skill in the art would have arrived at the instantly claimed variant, of Claim 21, having either the T65V or T65I substitution and at least two of the other mutations. Further, Beier suggests explicitly that it is clear to the skilled artisan that because each of these mutations provides an improved effect thus 2, 3, 4 etc. of the above substitutions may increase the effect.
MPEP§ 2143.I.(E) describes that in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), one of the exemplary rationales which support a conclusion of obviousness is "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success: “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 that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103."KSR, 550 U.S. at 421, 82 USPQ2d at 1397.”. In the instant case, the specific substitutions N61D, T65I, T65V, S82R, K107Q, T127S, and T127V as recited in claim 21 are taught in Beier to each provide improved stability to the same DNase parental polypeptide. Additional mutations, such as Q14R, D56I, D56L, and S68L, recited in the dependent claims, are also explicitly taught in Beier to provide improve stability.
Thus, variants of the DNase having these substitutions as claimed, which singularly provide stability as taught in Beier, are known to the art. It would have been a matter of routine optimization comprising selecting and combining these mutations, and testing the resulting mutants, to arrive at one or more of the instantly claimed combinations.
Regarding claims 22-24, the starting sequence of the DNase in Beier is 87.4% identical to that of the instantly claimed SEQ ID NO:1 (Appendix A below). With the substitutions applied, changing 3-8 positions, the variant remains within 87% identity to the instantly recited variant.
Regarding claim 27, because one or more of these specific mutations are taught in Beier, and taught to provide improved stability, inclusion of one or more of these, including for example one or more of Q14R, D56I, D56L, and S68L, would have been obvious for the same reasons described above.
In regards to claims 28 and 29, the combinations taught in Beier would have led one of ordinary skill to produce at least a variant with one of these combinations of mutations: Q14R+N61D+T65I+S82R+K107Q; Q14R+T65I+K107Q+T127S; N61D+T65I+S82R+T127S; or N61D+T65I+S82R+K107Q (as in claim 29).
In regards to claim 30, Beier teaches mutations made to the original parental sequence (SEQ ID NO:27 herein) that include T1I, S13Y, T22P, S25P, S27L, S39P, S42G, S57W, S59V, V76L, T77Y, Q109R, S116D, S144P, A147H, S167L, G175D ([0125]), thus teaching at least 5 of these positions may be present. Combining these mutations with those taught elsewhere would have been logical continuations of the suggestions in Beier.
Regarding claim 32, these are mutations which revert the sequence of the instant SEQ ID NO:1 to that of SEQ ID NO:1 in Beier, which teaches a DNase with one or more of these positions (i.e. a T in position 1, a S in position 13 and so on). Regardless of how the mutation or residue is specified, the resulting polypeptide of the instant invention would be indistinguishable from one having the original residue (i.e. that of SEQ ID NO:1 in Beier). See pg 9, line 19 - pg 10, line 3 of the instant disclosure regarding naming conventions for these substitutions.
From the teachings of Beier, it is apparent that there would have been a reasonable expectation of success in making the claimed polypeptide variants because the claimed parent DNase sequence is known to the art, the substitutions are taught to provide improved stability, and combinations of these are explicitly suggested in the reference.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the cited references, especially in the absence of evidence to the contrary.
Claims 21-32 are rejected under 35 U.S.C. 103 as being unpatentable over Beier et al. (US PGPub 20190256831) as applied to claim 21-24, 27-30, and 32 above, and further in view of Oestergaard et al. (US PGPub 20190127664, published 5/2/2019, issued 9/22/2020 as US 10,781,408), to include the rejections of claims 25-26 and 31.
Beier et al. makes obvious the DNase variant of claim 21 as described above.
Beier teaches a DNase variant having 87.4 identity to the claimed SEQ ID NO:1 and having at least two, three, four, five, six, seven, eight of the substitutions taught therein, including T65I or T65V, N61D, S82R, K107Q, and/or T127V ([0125]).
However, Beier does not teach a DNase variant having at least 90 or 95% sequence identity to SEQ ID NO:1 and the recited mutations (as in claims 25 and 26), nor does it teach a variant comprising 15-18 of the indicated residues in claim 31.
Oestergaard (US 20190127664) pertains to detergent compositions comprising polypeptide variants and teaches DNase variants exhibiting alterations relative to the parent DNase in one or more properties including: wash performance, detergent stability and/or storage stability (Abstract, [0002]). Oestergaard teaches sets of mutations that comprise, inter alia, T65V, T127V, N61D, and/or S82R (see [0169], [0174] and claims 1, 6, and 11). SEQ ID NO:28, comprising a DNase variant taught in Oestergaard et al. that is 96.5% identical to the instantly recited variant sequence of SEQ ID NO:1, according to the alignment of the two sequences accompanying this action (see Appendix B below). Oestergaard also teaches additional mutations, such as Q14R ([0170]), L33K ([0172]), Q48D ([0172]), D56I and D56L ([0172]), S66Y ([0172]), S68L ([0170]), as recited in the instant claim 27.
Regarding claims 30-32, the mutations taught in Oestergaard also include T1I, S13Y, T22P, S25P, S27L, S39P, S42G, S57W, S59V, V76L, T77Y, Q109R, S116D, T127L, S144P, A147H, S167L and G175D among others ([0169]-[0172])). When examining the sequence of SEQ ID NO:28 in Oestergaard, it is noted that the following are present: I at position 1, Y at position 13, P at position 22, L at position 27, G at position 42, W at position 57, V at position 59, L at position 76, Y at position 77, R at position 109, D at position 116, P at position 144, H at position 147, L at position 167, D at position 175. Further, according to the substitutions taught therein, the variant of Oestergaard can also include P in position 25, P in position 39, and L at position 181 (see [0169], at least). Oestergaard teaches producing a mutant protease according to SEQ ID NO:28 therein (analogous to SEQ ID NO:1 of the instant disclosure) and those having additional substitutions, then testing these substituted combinations for stability under stressed conditions and in the presence of various detergents and proteases (see e.g. Tables 2, 3, and 6). Oestergaard teaches that combinations of mutations, from among those discussed above results in variants with DNase activity and improved half-life stability. As one specific example, Oestergaard teaches a sequence having T1I, S13Y, T22P, S25P, S27L, L33K, S39P, S42G, D56L, S57W, S59V, T65V, S66Y, V76L, T77Y, Q109R, S116D, T127V, S144P, A147H, G162E, S167L, and G175D, which by lack of any specific mutation also includes an S at position 181 (e.g. akin to providing the L181S variant of the instant claims - see the last row of Tables 2, 3, and 4 and compare to SEQ ID NO:1 and 28 of Oestergaard), which has higher residual activity after the stress treatments (i.e. RAR after protease, sulfite, and detergent assay).
Thus, before the effective filing date of the claimed invention, it would have been prima facie obvious in view of the combined teachings of Beier and Oestergaard to produce a variant having at least three of the mutations T65V, T127V, N61D, and/or S82R, maintains at least 95% sequence identity to the sequence of SEQ ID NO:1 in the instant application as in claims 25 and 26, and also has 15-18 of the specific residues as recited in claims 31.
One would have been motivated by the teachings of Oestergaard, which teaches that DNase variants comprising substitutions of SEQ ID NO:28, comprising multiple mutations compared to SEQ ID NO:1 of Oestergaard (the parental DNase of B. cibi, the same as taught in Beier), and comprising ~97% sequence identity to SEQ ID NO:1 of the instant application, have increase stability and are resistant to protease, sulfite, and detergent exposure. There would have been a predictable benefit of obtaining a DNase with increased stability as taught in both Beier and Oestergaard when producing a DNase variant having T65V and at least two other mutations, especially one of T127V, N61D, and/or S82R because these are among the finite number of mutations taught in the prior art that increase the enzyme’s stability.
When producing a mutant protein variant, according to all of the teachings and motivation provided by Beier, selecting from among those mutations known in the art would have been a matter of judicious selection and routine optimization to one having ordinary skill in the art. Further, means for testing, assaying, and determining the suitability of such mutations are clearly taught in Oestergaard.
From the teachings of Oestergaard and Beier, it is apparent that there would have been a reasonable expectation of success in making the claimed DNase variants because the claimed DNase sequences are known to the art, the individual substitutions are taught to provide improved stability, and the benefits of combining such substitutions are taught in the references.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the cited references, especially in the absence of evidence to the contrary.
Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 21-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,774,293. Although the conflicting claims are not identical, they are not patentably distinct from each other because the scope of the '293 claims anticipates or renders obvious that of the instant claims.
Claim 1 of the reference patent recites a DNase variant polypeptide comprising one or more substitutions selected from an extensive list compared to SEQ ID NO: 1, wherein the variant has an amino acid sequence identity to the parent polypeptide of at least 90%, and the variant has DNase activity. Claim 2 of the reference patent recites additional substitutions including N61D, T65I, T65V, S82R, T127V. SEQ ID NO:1 of the reference patent claims is approximately 87% identical to the instantly claimed sequence (Appendix A below), and the substitutions are the same, thus the mutated variant sequence would predictably fall within the sequence identity claimed in the instant claims (i.e. at least 60% in claim 21).
The difference in the instant claim and the reference claims is that the instant claims require T65V/I and two additional mutations and the recited Markush groups of substitutions are different. Regardless, each of these features is encompassed by or is obvious over the instant claims, as the T65V and T65I mutations are recited in reference claim 2 along with two or more of the instantly claimed substitutions (e.g. N61D, S82R, and T127V). The Markush group of alternative substitutions recited in the '293 claims overlaps that of the instant claims. Further, the reference claims are comprising-type claims and have at least one or more substitutions, and claim 9 of the reference patent recites that the total number of amino acid substitutions compared to SEQ ID NO: 1 is 1-20. Therefore, the instantly claimed variants and the claimed features are obvious over the reference patent claims.
The instant claims 22-26 further limit the sequence identity to the instant variant sequence of SEQ ID NO:1, but it is evident that these variants are encompassed by the reference claims, encompassing variants having multiple substitutions compared to the wild-type parental sequence referenced therein and up to 20 different mutations. Thus, from a comparison of SEQ ID NO:1 in the instant application to that of the reference sequence, it is evident that a sequence encompassed by the reference claims having multiple mutations (up to 20) would fall under the claimed variants of at least 95% sequence identity to the instantly recited SEQ ID NO:1.
Instant claims 27-29 and 32 recite additional mutations, and combinations of mutations, that fall within or would have been obvious in view of the claimed subject matter of the ‘293 patent. See e.g. the mutations of “Q14R”, “D56I”, “D56L”, “S68L”.
Claims 28 and 29 recite substitution sets including “T65V+T127V+L181S”, which is encompassed by the mutations and sequences recited in the reference claim 2.
The specific positions recited in claim 32 correspond to many of the unmutated positions of the sequence in the reference claims (see e.g. T1I, S13Y, T22P, et cetera), thus variants comprising the same residues at the indicated positions are encompassed by the reference claims.
The instant claims 30-31 recite that the variants have 5 or more, or 15-18 of the amino acid residues in the recited positions. These positions correspond to specific substituted resides recited in reference claims 1 and 2 (e.g. those of T1I, S13Y, T22P, et cetera), and the reference subject matter includes variants having up to 20 mutations (see reference claim 9). Thus, the reference claims encompass variants according to the recitations of claims 30 and 31.
Claims 21-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,781,408. Although the conflicting claims are not identical, they are not patentably distinct from each other because the scope of the '408 claims anticipates or renders obvious that of the instant claims.
Claim 1 of the reference patent recites a variant of a DNase parent, which compared to a DNase with SEQ ID NO: 1, comprises two or more substitutions selected from an extensive list, which includes T127V, wherein the variant has a sequence identity to the polypeptide shown in SEQ ID NO: 1 or SEQ ID NO: 28 of at least 90% and wherein the variant has DNase activity. Claim 11 of the reference patent recites additional substitutions including T65I, T65V, S82R, and S181L.
SEQ ID NO:1 of the reference patent is approximately 87% identical to the instantly claimed sequence (Appendix A below), and the substitutions are the same, thus the mutated variant sequence would predictably fall within the sequence identity claimed in the instant claims (i.e. at least 60% in claim 21). Further, SEQ ID NO:28 of the reference patent is 96.5% identical to that of the instantly recited SEQ ID NO:1 (Appendix B below).
The difference in the instant claim and the reference claims is that the instant claims require T65V/I and two additional mutations (three total) and the recited Markush groups of substitutions are different. Regardless, each of these features is encompassed by or is obvious over the instant claims, as the T65V and T65I mutations are recited in reference claim 11 along with two or more of the instantly claimed substitutions (e.g. at least S82R and T127V). The Markush group of alternative substitutions recited in the reference claims 1 and 11 overlap with those of the instant claims. Therefore, the instantly claimed variants and the claimed features are obvious over the reference patent claims.
The instant claims 22-26 further limit the sequence identity to the instant variant sequence of SEQ ID NO:1, but it is evident that these variants are encompassed by the reference claims, encompassing variants having multiple substitutions. From the comparisons of SEQ ID NO:1 in the instant application to that of SEQ ID NO:1 and SEQ ID NO:28 in the reference sequence, it is evident that a sequence encompassed by the reference claims having multiple mutations falls under the claimed variants of at least 95% sequence identity to the instantly recited SEQ ID NO:1.
Instant claims 27-29 and 32 recite additional mutations, and combinations of mutations, that fall within or would have been obvious in view of the claimed subject matter of the ‘293 patent. See e.g. the mutations of “Q14R”, “D56I”, “D56L”, “S68L”. The reference claims also recite substitutions such as “Y77T”, “Q109R”, and “S116D”, which are opposite of the instant claims, but thus encompass those variants having Y77, Q109 and S116 residues, which are structurally identical to the substitutions of the claimed variants.
Claims 28 and 29 recite substitution sets including “T65V+T127V+L181S”, which is encompassed by the mutations and sequences recited in the reference claims (see claim 11).
The specific positions recited in claim 32 correspond to many of the unmutated positions of the sequence in the reference claims (see e.g. T1I, S13Y, T22P, et cetera), thus variants comprising the same residues at the indicated positions are encompassed by the reference claims.
The instant claims 30-31 recite that the variants have 5 or more, or 15-18 of the amino acid residues in the recited positions. These positions correspond to specific substituted resides recited in reference claims 1 and 2 (e.g. those of T1I, S13Y, T22P, S25P, et cetera). SEQ ID NO:28 of the reference claims includes 14 of these specified residues, and claims 1 and 11 recite the other 4 substitutions which are missing (i.e. S25P, S39P, T77Y, S181L). Thus, the reference claims encompass variants according to the recitations of claims 30 and 31.
Claims 21-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,447,723. Although the conflicting claims are not identical, they are not patentably distinct from each other because the scope of the '723 claims anticipates or renders obvious that of the instant claims.
Claim 1 of the reference patent recites a variant of a DNase parent, which compared to a DNase with SEQ ID NO: 1, comprises one or more substitutions selected from an extensive list, which includes N61D, T65I, T65V, S82R, T127V, wherein the variant has a sequence identity to the polypeptide shown in SEQ ID NO: 1 of at least 80% and the variant has DNase activity. Claim 4 of the reference patent recites that total number of alterations compared to SEQ ID NO: 1 is 1-20. SEQ ID NO:1 of the reference patent is approximately 87% identical to the instantly claimed sequence (Appendix A below), and the substitutions are the same, thus the mutated variant sequence would predictably fall within the sequence identity claimed in the instant claims (i.e. at least 60% in claim 21).
The difference in the instant claim and the reference claims is that the instant claims require T65V/I and two additional mutations (three total) and the recited Markush groups of substitutions are different. Regardless, each of these features is encompassed by or is obvious over the instant claims, as the T65V and T65I mutations are recited in reference claim 1 along with two or more of the instantly claimed substitutions (e.g. N61D, S82R, and/or T127V). The Markush group of alternative substitutions recited in the reference claim 1 overlaps with that of the instant claims. Therefore, the instantly claimed variants are obvious over the subject matter of the reference patent claims.
The instant claims 22-26 further limit the sequence identity to the instant variant sequence of SEQ ID NO:1, but it is evident that these variants are encompassed by the reference claims encompassing variants having multiple substitutions. A DNase variant according to the reference claims having multiple mutations, including those specified, encompasses the claimed variants having at least 95% sequence identity to the instantly recited SEQ ID NO:1 (when the specific mutations are applied to the reference SEQ ID NO:1).
Instant claims 27-29 and 32 recite additional mutations, and combinations of mutations, that fall within or would have been obvious in view of the claimed subject matter of the ‘293 patent. See e.g. the mutations of “Q14R”, “D56I”, “D56L”, “S68L” in claim 1. The reference claim 1 also recites substitutions such as “Y77T”, “Q109R”, “S116D” and “S181L”, which are opposite of the instant claims, but thus encompass those variants having Y77, Q109, S116, and S181 residues, which are structurally identical to the substitutions of the claimed variants.
Claims 28 and 29 recite substitution sets including “T65V+T127V+L181S”, which is encompassed by the mutations and sequences recited in the reference claims (see claim 11).
The specific positions recited in claim 32 correspond to many of the unmutated positions of the sequence in the reference claims (see e.g. T1I, S13Y, T22P, et cetera), thus variants comprising the same residues at the indicated positions are encompassed by the reference claims.
The instant claims 30-31 recite that the variants have 5 or more, or 15-18 of the amino acid residues in the recited positions. These positions correspond to specific substituted resides recited in reference claims 1 and 2 (e.g. those of T1I, S13Y, T22P, S25P, et cetera). Claim 1 of the reference patent recites additional substitutions including S25P, S39P, T77Y, S181L. Thus, the reference claims encompass variants according to the recitations of claims 30 and 31. Further, claim 4 indicates that the total number of mutations compared to SEQ ID NO:1 is up to 20 alterations, which would thus encompass the claimed variants, having the three substitutions required of the instant claim 21 and at least 15 more of the mutations (for a total of 18).
Claims 21-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,441,136. Although the claims at issue are not identical, they are not patentably distinct from each other because the scope of the '136 claims anticipates or renders obvious that of the instant claims.
Claim 1 of the reference patent recites a variant of a DNase parent, which compared to a DNase with SEQ ID NO: 1, comprises two or more substitutions selected from an extensive list, which includes T127V, wherein the variant has a sequence identity to the polypeptide shown in SEQ ID NO: 1 or SEQ ID NO: 28 of at least 90% and wherein the variant has DNase activity. Claim 11 of the reference patent recites additional substitutions including N61D, T65I, T65V, S82R, and S181L.
SEQ ID NO:1 of the reference patent is approximately 87% identical to the instantly claimed sequence (Appendix A below), and the substitutions are the same, thus the mutated variant sequence would predictably fall within the sequence identity claimed in the instant claims (i.e. at least 60% in claim 21). Further, SEQ ID NO:28 of the reference patent is 96.5% identical to that of the instantly recited SEQ ID NO:1 (Appendix B below).
The difference in the instant claim and the reference claims is that the instant claims require T65V/I and two additional mutations (three total) and the recited Markush groups of substitutions are different. Regardless, each of these features is encompassed by or is obvious over the instant claims, as the T65V and T65I mutations are recited in reference claim 8 along with two or more of the instantly claimed substitutions (e.g. at least N61D and S82R). The Markush group of alternative substitutions recited in the reference claims 1 and 8 overlap with those of the instant claims. Therefore, the instantly claimed variants and the claimed features are obvious over the reference patent claims.
The instant claims 22-26 further limit the sequence identity to the instant variant sequence of SEQ ID NO:1, but it is evident that these variants are encompassed by the reference claims, encompassing variants having multiple substitutions. From the comparisons of SEQ ID NO:1 in the instant application to that of SEQ ID NO:1 and SEQ ID NO:28 in the reference sequence, it is evident that a sequence encompassed by the reference claims having multiple mutations falls under the claimed variants of at least 95% sequence identity to the instantly recited SEQ ID NO:1. Claim 7 recites that the DNase variant comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the mutations selected from the group consisting of: T1I, S13Y, T22P, S25P, S27L, S39P, S42G, S57W, S59V, V76L, Q109R, S116D, T127V, S144P, A147H, S167L and G175D, of which all of these mutations appears to result in a variant having at least 95% identity to that of the instantly recited SEQ ID NO:1.
Instant claims 27-29 and 32 recite additional mutations, and combinations of mutations, that fall within or would have been obvious in view of the claimed subject matter of the ‘293 patent. See e.g. the mutations of “Q14R”, “D56I”, “D56L”, “S68L”. The reference claims also recite substitutions such as “Y77T”, “Q109R”, and “S116D”, which are opposite of the instant claims, but thus encompass those variants having Y77, Q109 and S116 residues, which are structurally identical to the substitutions of the claimed variants.
Claims 28 and 29 recite substitution sets including “T65V+T127V+L181S”, which is encompassed by the mutations and sequences recited in the reference claims 1, 8, and 9.
The specific positions recited in claim 32 correspond to many of the unmutated positions of the sequence in the reference claims (see e.g. T1I, S13Y, T22P, et cetera), thus variants comprising the same residues at the indicated positions are encompassed by the reference claims.
The instant claims 30-31 recite that the variants have 5 or more, or 15-18 of the amino acid residues in the recited positions. These positions correspond to specific substituted resides recited in reference claims 1 and 2 (e.g. those of T1I, S13Y, T22P, S25P, et cetera). SEQ ID NO:28 of the reference claims includes 14 of these specified residues, and claims 1 and 11 recite the other 4 substitutions which are missing (i.e. S25P, S39P, T77Y, S181L). Thus, the reference claims encompass variants according to the recitations of claims 30 and 31. Further, a variant having all the mutations in claim 7 appears to result in at least 15 of the instantly recited substitutions (as in claim 31), and the additional mutations are taught in claim 8.
Claim 21-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18/319,681.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application encompass or render obvious all of the instantly claimed subject matter.
Claim 1 of the reference patent (‘681) recites a detergent composition comprising a DNase variant which compared to the polypeptide of SEQ ID NO: 1 comprises two or more substitutions comprising N61D, T65I, T65V, S82R, K107Q, T127S, T127V, G149N, S164D, or L181S, wherein the variant has at least about 60% sequence identity to SEQ ID NO: 1 and has DNase activity. Thus, the composition of the ‘681 application comprises the polypeptide (DNase) variant of the instant claims.
Regarding the instant claims 22-26, reference claims 8-14 further limit the sequence identity of the variant, compared to the reference sequence (i.e. that of SEQ ID NO:1). Further, SEQ ID NO:1 of application 18/319,681 is 100% identical to that of the instant SEQ ID NO:1 (see Appendix C below). Thus the variant DNase of the ‘681 application encompasses a sequence and substitutions identical to those recited herein.
Regarding claim 27, reference claim 3 recites that the DNase variant further comprises at least one substitution comprising Q14R, Q14W, K21L, P25S, L33K, Q48D, D56I, D56L, S66Y, S68L, Y77T, S102Y, S106A, R109Q, R109T, D116S, D116W, T171W, L181T, or L181W, or a combination thereof, which is the same Markush group of the instant claim 27.
Regarding the instant claims 28 and 29, the recited Markush groupings of possible combination sets appear to substantially overlap between those of the reference claims 5 and 6. Although not identical, these groups of possible combination sets encompass the same subject matter. As an example, both the instant claim 28 and the reference claim 5 recite the combination of “Q14R+N61D+T65I+S82R+T127S+S164D”. Further, as an example, both instant claim 29 and reference claim 6 recite “N61D+T65I+S82R+K107Q”.
Regarding claims 30 and 31, reference claim 15 recites that the variant comprises at least 5 of the indicated amino acid residues in the following positions: I in position 1, Y in position 13, P in position 22, P in position 25, L in position 27, P in position 39, G in position 42, W in position 57, V in position 59, L in position 76, Y in position 77, R in position 109, D in position 116, P in position 144, H in position 147, L in position 167, D in position 175 and L in position 181. At least 5 encompasses the instantly claimed amount of 15-18 in claim 31, as all 18 positions of reference claim 15 could be the indicated residues.
Regarding instant claim 32, claim 16 of the reference application recites that the variant comprises one or more additional substitutions selected from I1T, Y13S, P22T, P25S, L27S, P39S, G42S, W57S, V59S,L76V, Y77T, R109Q, D116S, P144S, H147A, L167S and D175G, which is the same Markush group as instantly recited.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. It is noted that the ‘681 application has an earlier filing date (05/18/2023) than the instant application, however both the ‘681 and the instant applications have the same International filing date (3/10/2022) and both claim benefit to an effective filing date of 3/15/2021.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW TERRY MOEHLMAN whose telephone number is (571)270-0990. The examiner can normally be reached M-F 9am-5pm EST.
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/A.T.M./Examiner, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655
Appendix A: Alignment of SEQ ID NO:1 to the unmodified parent DNase
Search Query: SEQ ID NO:1
This sequence has >61 duplicates in the databases searched, including:
Sequence 1, US/16316393B
Patent No. 10774293
Publication No. US20190256831A1 (Referred to herein as “Beier et al.”)
Sequence 1, US/16171407A
Patent No. 10781408
Publication No. US20190127664A1 (Referred to herein as “Oestergaard et al.”)
Sequence 1, US/16171413A
Patent No. 10800997
Publication No. US20190127665A1
Sequence 1, US/16985302
Patent No. 11447723
Publication No. US20200362272A1
Sequence 28, US/16757557A
Patent No. 11441136
Publication No. US20200325461A1
Query Match 87.4%; Score 888; Length 182;
Best Local Similarity 90.6%;
Matches 164; Conservative 2; Mismatches 15; Indels 0; Gaps 0;
Qy 2 PPGTPSKSAAQYQLNALTVKPEGPMLGYSRDLFPHWIPQGGGCDTRQVVLKRDADWYVGN 61
||||||||||| |||||||| || | ||||||||||| || |||||||||||||| | ||
Db 2 PPGTPSKSAAQSQLNALTVKTEGSMSGYSRDLFPHWISQGSGCDTRQVVLKRDADSYSGN 61
Qy 62 CPVTSGSWYSYYDGLYFTNPSDLDIDHIVPLAEAWRSGASSWTTSKRRDFANDLDGPQLI 121
||||||||||||||: |||||||||||||||||||||||||||||||:|||||| |||||
Db 62 CPVTSGSWYSYYDGVTFTNPSDLDIDHIVPLAEAWRSGASSWTTSKRQDFANDLSGPQLI 121
Qy 122 AVSASTNRSKGDQDPSTWQPPRPGAHCGYSKWWISTKYKWGLSLQLSEKTALQDMLNSCL 181
|||||||||||||||||||||| || ||||||||||||||||||| ||||||| |||||
Db 122 AVSASTNRSKGDQDPSTWQPPRSGAACGYSKWWISTKYKWGLSLQSSEKTALQGMLNSCS 181
Qy 182 Y 182
|
Db 182 Y 182
Appendix B: Instant SEQ ID NO:1 vs SEQ ID NO: 28 (see references below)
Search Query: SEQ ID NO:1
This sequence has >3 duplicates in the databases searched, including:
Sequence 28, US/16171407A
Patent No. 10781408
Publication No. US20190127664A1
Sequence 28, US/16171413A
Patent No. 10800997
Publication No. US20190127665A1
Sequence 28, US/16757557A
Patent No. 11441136
Publication No. US20200325461A1
Query Match 96.5%; Score 980; Length 182;
Best Local Similarity 97.3%;
Matches 177; Conservative 0; Mismatches 5; Indels 0; Gaps 0;
Qy 1 IPPGTPSKSAAQYQLNALTVKPEGPMLGYSRDLFPHWIPQGGGCDTRQVVLKRDADWYVG 60
|||||||||||||||||||||||| ||||||||||||| |||||||||||||||||||||
Db 1 IPPGTPSKSAAQYQLNALTVKPEGSMLGYSRDLFPHWISQGGGCDTRQVVLKRDADWYVG 60
Qy 61 NCPVTSGSWYSYYDGLYFTNPSDLDIDHIVPLAEAWRSGASSWTTSKRRDFANDLDGPQL 120
|||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||
Db 61 NCPVTSGSWYSYYDGLTFTNPSDLDIDHIVPLAEAWRSGASSWTTSKRRDFANDLDGPQL 120
Qy 121 IAVSASTNRSKGDQDPSTWQPPRPGAHCGYSKWWISTKYKWGLSLQLSEKTALQDMLNSC 180
|||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 IAVSASVNRSKGDQDPSTWQPPRPGAHCGYSKWWISTKYKWGLSLQLSEKTALQDMLNSC 180
Qy 181 LY 182
|
Db 181 SY 182
Appendix C: Instant SEQ ID NO:1 vs SEQ ID NO:1 of US/18319681
Query Match 100.0%; Score 1016; Length 182;
Best Local Similarity 100.0%;
Matches 182; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 IPPGTPSKSAAQYQLNALTVKPEGPMLGYSRDLFPHWIPQGGGCDTRQVVLKRDADWYVG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 IPPGTPSKSAAQYQLNALTVKPEGPMLGYSRDLFPHWIPQGGGCDTRQVVLKRDADWYVG 60
Qy 61 NCPVTSGSWYSYYDGLYFTNPSDLDIDHIVPLAEAWRSGASSWTTSKRRDFANDLDGPQL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NCPVTSGSWYSYYDGLYFTNPSDLDIDHIVPLAEAWRSGASSWTTSKRRDFANDLDGPQL 120
Qy 121 IAVSASTNRSKGDQDPSTWQPPRPGAHCGYSKWWISTKYKWGLSLQLSEKTALQDMLNSC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 IAVSASTNRSKGDQDPSTWQPPRPGAHCGYSKWWISTKYKWGLSLQLSEKTALQDMLNSC 180
Qy 181 LY 182
||
Db 181 LY 182