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 .
This action is in response to the amendment filed 12/02/2025, in which claims 13 and 15 were amended and claim 14 was canceled. Claims 8-11, 13 and 15-32 are currently pending.
A restriction requirement was made final in the previous Office Action rendering claims 8-11, 19 and 21-32 withdrawn. Claims 13, 15-18 and 20 are currently under examination.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Response to Amendments - Drawings
The previous objection to the drawings has been withdrawn in view of Applicant’s newly filed drawings on 12/02/2025.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
This rejection was made in the Office action mailed 06/02/2025 and has been rewritten to address the amendment to the claims in the reply filed 12/02/2025.
Claims 16, 17 and 20 are rejected 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 depends. Claim 13 is drawn to "A polypeptide comprising the amino acid sequence set forth in any one of SEQ I DNOs: 1 and 4-13, wherein residue corresponding to residue 1003 of SEQ ID NO: 1 is substituted and residue corresponding to residue 661 of SEQ ID NO: 1 is substituted." Other than the specifically named substitutions in claim 13, the sequence of the recited sequence identifiers are required. The dependent claims provide further substitutions such that the original sequence outside of positions 661 and 1103 is no longer present. Thus, the dependent claims do not include all of the limitations of the claims from which they depend. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Amendments - Claim Rejections - 35 USC § 112
The previous rejection of claim 15 under 35 U.S.C. 112(d) as being in improper dependent form has been withdrawn in view of Applicant’s amendments to the claims filed on 12/02/2025.
The previous rejection of claims 16, 17 and 20 under 35 U.S.C. 112(d) as being in improper dependent form has been maintained in view of Applicant’s amendments to the claims filed on 12/02/2025 as well as Applicant’s traverse of the rejection.
Applicant’s arguments have been considered but are not found to be persuasive because Applicant argues that claims 15-17 and 20 depend from claim 13 and require the limitations of claim 13 as amended. However, claims 16, 17 and 20 do not require the claim limitations of 13. It would be remedial to amend the claims to recite the limitations as “further comprising”. For example, claim 16 should be amended to recite “The polypeptide of claim 13, further comprising residues corresponding to residues 695, 848 and 926 of SEQ ID NO: 1 are substituted with Alanine…”. Additionally, claim 17 should be amended to recite “The polypeptide of claim 16, further comprising the amino acid sequence set forth in SEQ ID NO: 1…”. Claim 20 is rejected for being dependent on claim 17 which is rejected under 35 U.S.C. 122(d) and does not require an amendment.
Response to Amendments - Claim Rejections - 35 USC § 102
The previous rejection of claims 13 and 18 under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Chen et al (WO 2017/093969 A1) has been withdrawn in view of Applicant’s amendments to the claims filed on 12/02/2025.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 13, 15 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (WO 2017/093969 Al). This is a NEW rejection necessitated by amendment filed on 12/02/2025.
Regarding claim 13, Chen teaches Cas9 molecules with conservative substitutions without affecting activity (e.g., page 561, line 21 to page 562, line 12). Chen teaches that conservative amino acid substitutions are ones in which one amino acid residue is replaced with another having a similar side chain, such as lysine and histidine (e.g., page 87, lines 24-27). Chen teaches the instant SEQ ID NO: 1 as SEQ ID NO: 6611 which is identified as Streptococcus pyogenes (See Appendix I; Pages 554-559). Chen teaches the combination of the mutations of SEQ ID NO: 6611 with substitutions for alanine at positions 661 and 1003 (Page 559, lines 5-25 and Page 560, Lines 21-30). Chen teaches the substitution alters the wild-type Cas9 molecule without abolishing or more preferably without substantially altering a Cas9 activity (e.g., cleavage activity) (Page 562, Lines 5-12).
Chen does not teach the specific histidine mutation at position 1003 of SEQ ID NO: 6611.
Due to Chen teaching the instant SEQ ID NO: 1 as SEQ ID NO: 6611 as well as the substitutions at positions 661 and 1003, it would have been obvious to one skilled in the art to substitute one conservative amino acid substitution for the other to achieve the predictable result of a mutant SpCas sequence. Thus, substitution of the position at 1003 of the original lysine for the histidine at position 1003 as taught by Chen would have been prima facie obvious to one of ordinary skill in the art, and thus the invention as claimed is unpatentable over the work of the prior art. Substitution of one known method for another known method, the methods having equivalent effect, is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results.
Regarding claim 15, Chen teaches the mutation of the Streptococcus pyogenes sequence at position 926 for alanine where each mutation is to an uncharged amino acid, such as alanine, where such mutations reduce the cutting by the Cas9 molecules at off-target sites (Page 559, lines 5-25 and Page 560, Lines 21-30).
Regarding claim 18, Chen teaches a pharmaceutical composition using the modified polypeptide sequence including pharmaceutically or physiologically acceptable carriers, diluents or excipients (Page 826, Lines 23-29).
Claims 16, 17 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (WO 2017 /093969 Al) in further view of Sternberg et al (Nature, Vol 527, pgs. 110-114; 2015). This is a previous rejection made in the Office Action filed on 06/02/2025 and rewritten to address the amendments to the claims filed on 12/02/2025.
The teachings of Chen are described and applied above.
Regarding claims 16 and 17, Chen teaches Cas9 molecules with conservative substitutions without affecting activity (e.g., page 561, line 21 to page 562, line 12). Chen teaches that conservative amino acid substitutions are ones in which one amino acid residue is replaced with another having a similar side chain, such as lysine and histidine (e.g., page 87, lines 24-27). Chen teaches the mutation of the Streptococcus pyogenes sequence at positions 695, 848 and 926 for alanine where each mutation is to an uncharged amino acid, such as alanine, where such mutations reduce the cutting by the Cas9 molecules at off-target sites (Page 559, lines 5-25 and Page 560, Lines 21-30).
Chen does not teach the mutations of positions 923 to methionine as well as position 924 to valine.
Sternberg teaches the substitution of positions 923 and 924 with an amino acid mutation (Page 112, Column 2). Sternberg teaches a substitution at positions 923 and 924 with an amino acid that results in the disruption of the alpha helix formation (e.g., disruption of the Ruv/HNH linker) results in a conformational change of the HNH domain that is not communicated to the RuvC domain and the RuvC domain therefore does not cleave the target nucleic acid or cleaves with reduced efficiency/rate (Page 112, Column 2). Sternberg teaches this effect could be reversed with the corresponding alanine mutations (Page 112, Column 2 and Figure 4c).
Sternberg does not specifically teach the modification of methionine at position 923.
Due to Chen teaching Cas9 molecules with conservative substitutions without affecting
activity wherein conservative amino acid substitutions are ones in which one amino acid residue is replaced with another having a similar side chain, such as lysine and histidine as well as the mutation of the Streptococcus pyogenes sequence at positions 695, 848 and 926 for alanine where each mutation is to an uncharged amino acid, such as alanine, where such mutations reduce the cutting by the Cas9 molecules at off-target sites and Sternberg teaching the substitution of positions 923 and 924 with an amino acid mutation such as an alanine mutation, it
would have been obvious to one skilled in the art to substitute one conservative amino acid
substitution for the other to achieve the predictable result of a mutant SpCas sequence. Thus,
substitution of the positions 923 and 924 of glutamine for methionine and threonine for valine,
respectively, as taught by Chen and Sternberg would have been prima facie obvious to one of
ordinary skill in the art, and thus the invention as claimed is unpatentable over the work of the
prior art. Substitution of one known method for another known method, the methods having
equivalent effect, is considered to be obvious, absent a showing that the result of the substitution
yields more than predictable results.
One would have been motivated to make such a modification in order to receive the
expected benefit of retaining the function of the modified SpCas9 using catalytically inactive
substitutions as taught by Chen and Sternberg.
Regarding claim 20, the instant specification defines examples of “physiologically acceptable excipient” as water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring and coloring agents, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with the intended use [0047].
Chen teaches a pharmaceutical composition using the modified polypeptide sequence including pharmaceutically or physiologically acceptable carriers, diluents or excipients (Page 826, Lines 23-29).
Chen does not teach the specific composition comprising the polypeptide of claim 17 and a physiologically acceptable excipient.
Due to Chen teaching Cas9 molecules with conservative substitutions without affecting
activity wherein conservative amino acid substitutions are ones in which one amino acid residue is replaced with another having a similar side chain, such as lysine and histidine as well as the mutation of the Streptococcus pyogenes sequence at positions 695, 848 and 926 for alanine where each mutation is to an uncharged amino acid, such as alanine, where such mutations reduce the cutting by the Cas9 molecules at off-target sites and Sternberg teaching the substitution of positions 923 and 924 with an amino acid mutation such as an alanine mutation, it
would have been obvious to one skilled in the art to substitute one conservative amino acid
substitution for the other to achieve the predictable result of a mutant SpCas sequence. Thus,
substitution of the positions 923 and 924 of glutamine for methionine and threonine for valine,
respectively, as taught by Chen and Sternberg would have been prima facie obvious to one of
ordinary skill in the art, and thus the invention as claimed is unpatentable over the work of the
prior art. Substitution of one known method for another known method, the methods having
equivalent effect, is considered to be obvious, absent a showing that the result of the substitution
yields more than predictable results.
One would have been motivated to make such a modification in order to receive the
expected benefit of retaining the function of the modified SpCas9 using catalytically inactive
substitutions as taught by Chen and Sternberg.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claims 14 and 15 under 35 U.S.C. 103 as being unpatentable over Chen et al (WO 2017/093969 A1) has been withdrawn in view of Applicants cancelation of claim 14 and the amendments to claim 15 filed on 12/02/2025.
The previous rejection of claims 16, 17 and 20 under 35 U.S.C. 103 as being unpatentable over Chen et al (WO 2017/093969 A1) in view of Sternberg et al (Nature, Vol 527, pgs. 110-114; 2015) has been maintained in view of Applicants arguments and amendments to the claims filed on 12/02/2025.
Applicant’s arguments have been fully considered but have not been found to be persuasive because Applicant argues that the combination of Chen and Sternberg does not lead one to the claims, absent impermissible hindsight.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that Chen or Sternberg discloses the specific combination of mutations. Applicant continues to argue that there is no guidance provided from Chen or Sternberg to make these substitutions.
However, as stated above, due to Chen teaching the instant SEQ ID NO: 1 as SEQ ID NO: 6611 as well as the substitutions at positions 661 and 1003, it would have been obvious to one skilled in the art to substitute one conservative amino acid substitution for the other to achieve the predictable result of a mutant SpCas sequence. Thus, substitution of the position at 1003 of lysine for the histidine at position 1003 as taught by Chen would have been prima facie obvious to one of ordinary skill in the art, and thus the invention as claimed is unpatentable over the work of the prior art. Substitution of one known method for another known method, the methods having equivalent effect, is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results.
Applicant argues that the admission that Sternberg’s mutation from native Glu (923) and threonine (924) results in a mutant that does not cleave the target nucleic acid or cleaves with reduced efficiency undermines the Examiner’s assertion that it would have been obvious to make conservative substitutions to achieve predictable results, since the Examiner also recognizes that blocked nuclease activity could be reversed in the mutants in Sternberg, by introducing alanine at positions 923 and 924. Applicant continues to argue that why then would one introduce a non-conservative mutation of the alanine position 923 which Sternberg discloses activity, with methionine with the expectation of retaining nuclease activity. Applicant insists that Chen teaches that replacing alanine with methionine is not a conversative substitution and therefore one would not expect to reverse the blocked nuclease activity taught by Sternberg and therefore Sternberg teaches away.
This argument is not persuasive because due to Chen teaching Cas9 molecules with conservative substitutions without affecting activity wherein conservative amino acid substitutions are ones in which one amino acid residue is replaced with another having a similar side chain, such as lysine and histidine as well as the mutation of the Streptococcus pyogenes sequence at positions 695, 848 and 926 for alanine where each mutation is to an uncharged amino acid, such as alanine, where such mutations reduce the cutting by the Cas9 molecules at off-target sites and Sternberg teaching the substitution of positions 923 and 924 with an amino acid mutation such as an alanine mutation, it would have been obvious to one skilled in the art to substitute one conservative amino acid substitution for the other to achieve the predictable result of a mutant SpCas sequence. Thus, substitution of the positions 923 and 924 of glutamine for methionine and threonine for valine, respectively, as taught by Chen and Sternberg would have been prima facie obvious to one of ordinary skill in the art, and thus the invention as claimed is unpatentable over the work of the prior art. Substitution of one known method for another known method, the methods having equivalent effect, is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. One would have been motivated to make such a modification in order to receive the expected benefit of retaining the function of the modified SpCas9 using catalytically inactive substitutions as taught by Chen and Sternberg.
Moreover, Chen teaches that conservative amino acid substitutions are ones in which one amino acid residue is replaced with another having a similar side chain, such as within the side chain families (e.g., page 87, lines 24-27). Based off of Chen’s teachings on Page 87, Lines 24-27, Chen teaches that the amino acids from the same side chain family, such as the nonpolar side chain family which contains both alanine and methionine, would result in a conservative amino acid substitution. Therefore, neither Chen nor Sternberg teaches away from the instant claims as they are currently written.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/ Examiner, Art Unit 1637
/CELINE X QIAN/ Primary Examiner, Art Unit 1637