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 .
Application Status
This action is written in response to applicant’s correspondence received on 2/13/2026. Claims 1-3, 7, 10, 14, 18-23, 25-26, 51, 53-54, 56, 75, 78, 98, 100-107, 137, 145, 151-152, 161, 168, and 171 are pending. Claims 1, 22, 51, and 75 have been amended. Claims 100-107, 137, 145, 151-152, 161, 168, and 171 are withdrawn from consideration. Claims 1-3, 7, 10, 14, 18-23, 25-26, 51, 53-54, 56, 75, 78, 98 are currently under examination.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. This Office Action is Final.
Claim Rejections - 35 USC § 103 – Previous Rejection Reinstated after Applicant Amendment
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.
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 1-3, 7, 14, 18, 20-22, 26, 51, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (WO 2018/027078 A1, provided in the IDS filed 11/10/2020) and further in view of Bartels (Bartels CL et al. Am J Transl Res. 2009 Aug 10;1(4):406-11, of record).
Summary of Claims and the 103 Rejection
The presently recited subject matter of claim 1, which is also recited in the independent claims, will be summarized here. Claim 1 now recites that the SERPINA1 gene comprises a SNP mutation rendering a lysine at position 342, which is corrected to a glutamic acid (“E”) at position 342. Note that, per SEQ ID NO: 296, the wildtype version of SERPINA, the wildtype sequence comprises an E at position 342. In this sense, claim 1 is now directed to correcting a pathogenic mutation (K at 342) to a wildtype, functional version of the protein (i.e., “E” at position 342). In addition, claim 1 also recites that the alterations result in a Glycine (“G”) at position 341. In wildtype form, position 341 comprises a “D” at this residue. Thus, the overall corrected gene recited in claim 1 is a reversion of the pathogenic allele K342 to a wildtype form, where the neighboring allele 341 is converted to G (i.e., a D341G substation). As will be discussed further, it is the position of the office that it would be obvious to correct the known pathogenic allele E342K to its native form, in order to alleviate the pathogenicity of this mutant allele. Furthermore, the mutation at position 341 does not appear to have any effect and is not a pathogenic allele site. As such, mutating position 341 to another amino acid residue is the simple substitution of one known allele for another with predictable results, absent any evidence to the contrary (see rejection, below)
Rejection of Claims
Regarding claim 1, Liu teaches a method of editing a SERPINA1 polynucleotide comprising a single nucleotide polymorphism (SNP) associated with alpha-1 Anti-Trypsin Deficiency (A1AD) (paragraph 353-354 and Table 2, page 357, second-to-last row of Table 2). Liu teaches that the method comprises contacting
the SERPINA1 polynucleotide with a base editor in complex with one or more guide polynucleotides (paragraph 360). Liu teaches a base editor comprising a
polynucleotide programmable DNA binding domain and an adenosine deaminase domain (paragraph 360). Liu teaches that one or more of the guide polynucleotides target the base editor to effect an alteration to correct “G to A” and “C to T” pathogenic mutations (paragraph 354).
Liu, while teaching a method of editing a SERPINA1 gene using programmable base editors which can effect G to A and C to T mutations to correct pathogenic alleles, does not expressly recite A/T to G/C alterations of a SNP associated with A1AD but instead teaches correction of C to T alterations in the SERPINA1 gene to treat A1AD (paragraphs 353-354, Table 2 page 357 second-to-last row, paragraph 360). Liu does not specifically teach that the SNP is a lysine at position 342, or that the mutation renders Glycine (G) at position 341 and Glutamic Acid (E) at position 342.
Bartels is a research article focused on the detection of pathogenic alleles associated with A1AD (Title, Abstract, and see document). Bartels and Liu therefore directly overlap in subject matter because both concern the same gene (SERPINA1) and the role that SNP mutations in SERPINA1 have on disease states. Bartels teaches that the PI*Z mutation in the SERPINA1 gene is the most common causes of A1AD (Abstract). Furthermore, Bartels teaches that the PI*Z mutation results from a “G to A” SNP variation (Table 1, page 407). Thus, Bartels teaches that one of the most common causes of A1AD is a “G to A” mutation in SERPINA1 (Table 1 and Abstract). Furthermore, Bartels teaches that the Pi*Z mutant results in the E342K genotype (page 407, left column, first paragraph). Thus, Bartels teaches that the wildtype residue at position 342 is “E,” and that the most common pathogenic mutation is a mutation of E to K at position 342 (i.e., E342K).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the mutation target of the editing method taught by Liu to instead effect an A/T to G/C alteration because Bartels teaches that the most common causes of A1AD is such a mutation (Table 1 of Bartels, i..e, an E342K mutation). Thus, a practitioner of ordinary skill would be motivated to incorporate the teachings of Bartels into the methods of Liu so that they could treat one of the most commonly known SNP mutations which causes A1AD because treating A1AD by targeting mutations in SERPINA1 is the goal of Liu (Bartels Abstract and Table 1, Liu paragraphs 353-354, 360, Table 2 page 357 second-to-last line). Furthermore, such a combination would amount to the simple substitution of one known prior art element for another with predictable results. In the present case, a practitioner would substitute the C to T correction in the SERPINA1 gene taught by Liu with the A to G correction taught by Bartels. Furthermore, the results are predictable because Liu teaches that their methods are compatible with making A to G mutations (paragraph 354).
Regarding the limitation that position 341 is converted to a Glycine, (which is “D” in wildtype form) this limitation is not viewed as inventive, as such a conversion of position 341 to G is the simple substitution of one known element for another with predictable results. In the present case, a practitioner would be substituting the wildtype “D” for a “G,” where the selection is made from one of twenty known amino acid options. Furthermore, the residue position 341 is not a pathogenic allele site; position 342 is the pathogenic allele site. As such, absent any evidence to the contrary, there is no indication that such a mutation would yield any effects upon a A1AT gene product/protein. The results are therefore predictable and do not appear to have any unpredictable effect. For instance, as seen in Figure 3C of the instant Application, wildtype, D341G, and pathogenic E342K variants were assessed for elastatse inhibition. The wildtype outperformed the D341G variant as evidenced by the increase in concentration needed for the D341G mutant to achieve comparable elastase inhibition compared with wildtype. These results are not unexpected. With the D341G mutation, the Applicant has simply mutated the pathogenic allele (E342K) to its native wildtype form, and mutated the neighboring allele to G, to yield slightly worse enzyme activity compared with a wildtype protein (Figure 3C). These results are not unexpected: for instance, the D341G mutation did not render superior enzyme characteristics, it only yielded enzyme function that was slightly worse than the performance of regular wildtype functionality, Figure 3C. Residue 341 is not associated with a pathogenic allele state, and so slightly diminished enzyme kinetics upon alteration of this residue are not unexpected.
Regarding claim 2, Liu teaches that the contacting of the SERPINA1 polynucleotide is in a cell, a eukaryotic cell, a mammalian cell, and/or a human cell (paragraph 232 and 236).
Regarding claim 3, Liu teaches that the cell is in vivo or ex vivo (paragraph 236).
Regarding claim 7, Liu teaches that the SpCas9 comprises a modified SpCas9 having an altered PAM specificity (e.g., paragraph 281). Furthermore, Liu teaches that Cas9 can be a modified version of Cas9 (e.g., paragraph 277).
Regarding claim 14, Liu teaches that polynucleotide programmable DNA binding domain is a nuclease inactive or nickase variant (paragraph 277).
Regarding claim 18, Liu teaches that the adenosine deaminase can be a TadA deaminase (e.g., paragraph 332 and claim 4).
Regarding claims 20 and 21, Liu teaches that the base editor is in complex with a sgRNA which target various complementary sequences (e.g., Table 8, paragraph 159 and 189-196). As discussed above, Liu also teaches targeting the SERPINA1 gene to effect a base edit (Table 2, page 357, second-to-last row). It is therefore obvious to target SERPINA1 using complementary sgRNA based on the teachings of Liu, so that the suggestion of Liu to target SERPINA1 to treat A1AD could be accomplished (paragraphs 353-354, 360, Table 2 page 357, second-to-last row).
Regarding claim 22, Liu teaches cells that are produced following their methods (paragraph 236). Furthermore, the specific alterations recited in claim 22 to the SERPINA gene are the same as claim 1. A discussion of the rejection of the limitations of claim 1 are given above and incorporated here to address the limitations of the cell of claim 22.
Regarding claim 26, Liu teaches obtaining cells from subjects suffering from diseases (paragraph 236), and further teaches that one of these diseases can be A1AD (Table 2, page 357, second-to-last row, page 165 line 10).
Regarding claim 51, as discussed above, the combination of Liu and Bartels renders obvious the cell of instantly recited claim 22. Liu further teaches the introduction of a cell to a subject, where the cell has been treated following their methods in order to treat a genetic deficiency (paragraph 236). Liu further teaches that A1AD can be one such genetic deficiency (page 165 line 10, Table 2 page 357, second-to-last row).
Regarding claim 53, Liu teaches delivering a base editor and one or more guide nucleotides to a cell and also teaches that the cell can be from the subject (paragraph 236, 300, 353-354).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Liu (WO 2018/027078 A1, provided in the IDS filed 11/10/2020) and Bartels (Bartels CL et al. Am J Transl Res. 2009 Aug 10;1(4):406-11, of record) as applied to claims 1-3, 7, 14, 18, 20-22, 26, 51, and 53 above, and further in view of Kleinstiver (Kleinstiver BP et al. Nature. 2015 Jul 23;523(7561):481-5, provided in IDS filed 5/4/2022) and Anders (Anders C et al. Mol Cell. 2016 Mar 17;61(6):895-902, of record).
Regarding claims 1-3, 7, 14, 18, 20-22, 26, 51, and 53, these claims are rendered obvious by the combination of Liu and Bartels as discussed above.
Regarding claim 10, Liu teaches SpCas9 variants, specifically where the Cas9 proteins can be rendered with reduced PAM motif exclusivity (page 79 final paragraph to page 80, first paragraph). Liu references Kleinstiver in reference to some of the types of Cas9 variants that they envision for use with their methods (page 80, line 7). It is therefore reasonable to include the teachings of Kleinstiver with the teachings of Liu.
Kleinstiver, and by extension Liu, teaches that SpCas9 nucleases can be modified at specific residues in order to broaden their PAM site specificity, a trait which would be useful for adopting Cas9 proteins to broader genome editing applications (Abstract and see document). Kleinstiver teaches that the S1136 residue is a residue involved with the 3rd base position of the PAM recognition site (page 15, Extended Data Figure 5A and 5B). Furthermore, Kleinstiver teaches that S1136 is tolerant to mutations while still retaining the function of the Cas9 molecule (Figure 5B). Kleinstiver teaches that mutations associated with PAM recognition sites may broaden the use of Cas9 molecules, and further reduced to practice S1136 mutants by demonstrating that such mutants retain their functionality (Abstract, see document, and Figures 5A and 5B).
Liu, Bartels, and Kleinstiver do not specifically teach the S1136Q mutation, or the D1332A mutation.
Anders is a research article that teaches the structural plasticity of PAM recognition sites in engineered Cas9 variants (Title, Abstract, see document). Thus, Anders and Liu directly overlap because Liu, by teaching SpCas9 variants with enhanced PAM recognition and also referencing Kleinstiver also teaches the engineering of Cas9 variants to broaden PAM site recognition (Liu page 80 line 7, Kleinstiver Abstract and Figure 5). Anders teaches that Cas9 proteins can be engineered to recognize alternative PAMs in order to improve the limitations of strict PAM site requirements (Abstract). Furthermore, Anders teaches that D1332 substitutions can be made in the context of engineering PAM sites (page 899, left column final paragraph and Figure 4). Furthermore, Anders teaches reduction to practice D1332K mutants and teaches that such mutations render functional Cas9 enzymes (Figure 4C, see QQR1 cleavage). Thus, D1332 is a residue that is significant in PAM site recognition and is also tolerant to mutation (page 899, left column final paragraph and Figure 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the SpCas9 variants taught by Liu to comprise D1332A mutations and S1136Q mutations because such a combination is obvious to try, where a practitioner is selecting from a finite number of predictable options with a reasonable expectation of success. In the present case, Liu has already taught motive to mutate SpCas9 mutants by referencing Kleinstiver, who teaches that variant Cas9 mutants have a benefit of broadening PAM site recognition (Kleinstiver Abstract, Liu page 80 line 7). Furthermore, D1332 and S1136 Cas9 variants are already known, are further known to be important residues for PAM recognition, and are further known to be residues tolerant to mutation as taught by Kleinstiver and Anders (Kleinstiver Figure 5, S1136, and Anders page 899 left column final paragraph and Figure 4). Thus, to arrive at D1332A and S1136Q variants, a practitioner would be choosing from 1 of 20 amino acids, where such amino acid substitutions would have a reasonable expectation of success given that the recited residues are known to be tolerant to mutations. Furthermore, a practitioner would be motivated to create such variants in order to broaden the PAM site recognition of Cas9, and could arrive at such variants through routine laboratory optimization given the motivational teachings of Anders, Liu, and Kleinstiver (above).
Claims 19 is rejected under 35 U.S.C. 103 as being unpatentable over Liu (WO 2018/027078 A1, provided in the IDS filed 11/10/2020) and Bartels (Bartels CL et al. Am J Transl Res. 2009 Aug 10;1(4):406-11, of record) as applied to claims 1-3, 7, 14, 18, 20-22, 26, 51, and 53 above, and further in view of Gaudelli (Gaudelli NM et al. Nature. 2017 Nov 23;551(7681):464-471, provided in IDS filed 5/4/2022).
Regarding claims 1-3, 7, 14, 18, 20-22, 26, 51, and 53, as discussed above the combination of Liu and Bartels renders obvious these claims.
Liu teaches the use of TadA deaminases to be used in their constructs (page 332 and claim 4).
Liu does not specifically teach that the deaminase is TadA*7.10.
Gaudelli is a research article that focuses on programmable base editors which effect A/T to G/C changes and the relevance of such transitions in the state of diseases (Title, Abstract, and see document). Thus, the subject matter of Liu, Bartels, and Gaudelli directly overlaps in field of endeavor and subject matter because each of these prior art documents concerns base mutations and their roles in disease (see documents). Furthermore, Gaudelli teaches TadA deaminases to be used as programmable base editors, and specifically teaches that incorporating TadA*7.10 into adenine base editor constructs “substantially improved editing efficiencies,” (page 469, left column, third paragraph). Thus, Gaudelli teaches not only that TadA*7.10 is known to be functional with adenine base editors but is also known to offer known advantages by improving editing efficiencies (page 469, left column, third paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the TadA component taught by Liu to be a TadA*7.10 deaminase because the use of the TadA*7.10 deaminase is already known in the art to offer advantages as taught by Gaudelli (page 469, left column, third paragraph). Thus, a practitioner would be motivated to use TadA*7.10. Furthermore, such a combination of prior art elements is the simple substitution of one known element for another with predictable results. In the present case, a practitioner would substitute the TadA taught by Liu with the TadA*7.10 taught by Gaudelli, with the specific motivation of improving editing efficiency, as taught by Gaudelli (page 469, left column, third paragraph). Furthermore, the results are predictable because Liu already teaches that TadA deaminase are compatible with their methods (Liu, e.g., paragraph 2).
Claims 23, 25, 54, 56, 75, 78, and 98 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (WO 2018/027078 A1, provided in the IDS filed 11/10/2020) and Bartels (Bartels CL et al. Am J Transl Res. 2009 Aug 10;1(4):406-11, of record) as applied to claims 1-3, 7, 14, 18, 20-22, 26, 51, and 53 above, and further in view of Shen (WO 2017/165862 A1, provided in the IDS filed 11/10/2020).
Regarding claims 23, a discussion of claims 1-3, 7, 14, 18, 20-22, 26, 51, and 53 is given above and incorporated herein with respect to overlapping claim limiations.
Regarding claims 23, Liu teaches obtaining cells from a subject and reintroducing the cells into the patient following their methods to correct genetic deficiencies such as those caused by SERPINA1 mutations (paragraph 236, paragraphs 353-354, 360, Table 2 page 357, second-to-last row).
Regarding claim 54, Liu teaches obtaining cells from a subject and reintroducing the cells into the patient following their methods to correct genetic deficiencies such as those caused by SERPINA1 mutations (paragraph 236, paragraphs 353-354, 360, Table 2 page 357, second-to-last row).
Regarding claim 75, Liu teaches producing cells, where the cells are produced following their methods (paragraph 236). Liu teaches a method of editing a SERPINA1 polynucleotide comprising a single nucleotide polymorphism (SNP) associated with alpha-1 Anti-Trypsin Deficiency (A1AD) (paragraph 353-354 and Table 2, page 357, second-to-last row of Table 2). Liu teaches that the method comprises contacting the SERPINA1 polynucleotide with a base editor in complex with one or more guide polynucleotides (paragraph 360). Liu teaches a base editor comprising a polynucleotide programmable DNA binding domain and an adenosine deaminase domain (paragraph 360). Liu teaches that one or more of the guide polynucleotides target the base editor to effect an alteration to correct “G to A” and “C to T” pathogenic mutations (paragraph 354).
Regarding claim 98, Liu teaches that the base editor is in complex with a sgRNA which target various complementary sequences (e.g., Table 8, paragraph 159 and 189-196). As discussed above, Liu also teaches targeting the SERPINA1 gene to effect a base edit (Table 2, page 357, second-to-last row). It is therefore obvious to target SERPINA1 using complementary sgRNA based on the teachings of Liu, so that the suggestion of Liu to target SERPINA1 to treat A1AD could be accomplished (paragraphs 353-354, 360, Table 2 page 357, second-to-last row).
Liu, while teaching a method of editing a SERPINA1 gene using programmable base editors which can effect G to A and C to T mutations to correct pathogenic alleles, does not expressly recite A/T to G/C alterations of a SNP associated with A1AD but instead teaches correction of C to T alterations in the SERPINA1 gene to treat A1AD (paragraphs 353-354, Table 2 page 357 second-to-last row, paragraph 360). Liu does not specifically teach that the SNP is a lysine at position 342, or that the mutation renders Glycine (G) at position 341 and Glutamic Acid (E) at position 342.
Furthermore, Liu does not teach that the cells are hepatocytes.
Bartels is a research article focused on the detection of pathogenic alleles associated with A1AD (Title, Abstract, and see document). Bartels and Liu therefore directly overlap in subject matter because both concern the same gene (SERPINA1) and the role that SNP mutations in SERPINA1 have on disease states. Bartels teaches that the PI*Z mutation in the SERPINA1 gene is the most common causes of A1AD (Abstract). Furthermore, Bartels teaches that the PI*Z mutation results from a “G to A” SNP variation (Table 1, page 407). Thus, Bartels teaches that one of the most common causes of A1AD is a “G to A” mutation in SERPINA1 (Table 1 and Abstract).
Bartels teaches that A1AD is a liver disease arising from mutations in SERPINA1 (Abstract, Introduction first paragraph). Bartels teaches that G to A mutations in SERPINA1 are known to be associated with hepatocyte death (Table 1). Bartels therefore teaches a motivation to target liver cells for treatment of A1AD associated with SERPINA1 mutations (Abstract, Introduction first paragraph, and Table 1).
Regarding claim 25, Bartels teaches that hepatocytes produce A1AT (Abstract).
Furthermore, regarding claim 23, Shen teaches a method for treating or preventing A1AD, including A1AD caused by E342K in the SERPINA1 gene (page 38, fourth paragraph and see document). Thus, the teachings of Liu, Bartels, and Shen directly overlaps in field of endeavor and subject matter. Furthermore, Shen teaches that their methods utilize CRISRP-Cas-mediated genome editing to correct target positions in SERPINA1 (page 38, fourth paragraph). Additionally, Shen teaches that their methods involve removing and editing cells from subjects, where the cells are hepatocytes and/or embryonic stem cells or induced pluripotent stem cells (page 143, paragraphs 3-5). Shen therefore teaches that it is already a known method to target hepatocytes with genomic editing, where the cells are taken from subjects and reintroduced to the patients, specifically to treat A1AD by targeting SERPINA1 (page 38, fourth paragraph, page 143 paragraphs 3-5).
Regarding claim 25, Shen also teaches that hepatocytes produce A1AT (e.g., page 45 first paragraph).
Regarding claim 56, Shen teaches that A1AD is characterized by the production of toxic/mutant A1AT polypeptide, where the methods of Shen mutate this mutation to a wild-type form of the A1AT polypeptide (page 39, second paragraph). Thus, the cells taught by Shen comprise a mutation in the A1AT polypeptide (page 39, second paragraph).
Regarding claim 75, Shen teaches that their methods involve removing and editing cells from subjects, where the cells are hepatocytes and/or embryonic stem cells or induced pluripotent stem cells, “iPS,” (page 143, paragraphs 4-5). Shen teaches that such iPS cells can be obtained from a subject in need of modification of a genetic deficiency (page 143, final paragraph). Shen therefore teaches that it is already a known method to target hepatocytes with genomic editing, where the cells are taken from subjects and reintroduced to the patients, specifically to treat A1AD by targeting SERPINA1 (page 38, fourth paragraph, page 143 paragraphs 4-5). Shen teaches differentiating the iPS cells into hepatocytes (page 143, final paragraph).
Regarding claim 78, Shen teaches that the hepatocyte progenitor is obtained from a subject with A1AD (page 143, paragraphs 3-5 and page 38, fourth paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the subject cells taught by Liu to be liver cells (hepatocytes) as taught by both Bartels and Shen because A1AD associated with SERPINA1 mutations is known to cause liver disease (Bartels Abstract, Introduction, Table 1) and furthermore targeting hepatocytes for genomic editing using CRISPR systems to treat A1AD is a known method taught by Shen (page 38 fourth paragraph, page 143 paragraphs 4-5). Thus, given that Liu has already taught obtaining cells and reintroducing them into a subject, it would be obvious to a practitioner to use liver cells (hepatocytes) in the method of Liu to treat A1AD using the methods of Shen because it was already known that A1AD affects the liver (Bartels, Abstract, Shen page 38 fourth paragraph). A practitioner would therefore be motivated to practice the method of Liu in hepatocytes, as taught by Shen, in order to treat the disease caused by mutation in SERPINA1 (i.e., the goal of Liu).
Furthermore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the mutation target of the editing method taught by Liu to instead effect an A/T to G/C alteration in order to create a cell because Bartels teaches that one of the most common causes of A1AD is such a mutation (Table 1 of Bartels). Thus, a practitioner of ordinary skill would be motivated to incorporate the teachings of Bartels into the methods of Liu so that they could treat one of the most commonly known SNP mutations which causes A1AD because treating A1AD by targeting mutations in SERPINA1 is the goal of Liu (Bartels Abstract and Table 1, Liu paragraphs 353-354, 360, Table 2 page 357 second-to-last line). Furthermore, such a combination would amount to the simple substitution of one known prior art element for another with predictable results. In the present case, a practitioner would substitute the C to T correction in the SERPINA1 gene taught by Liu with the A to G correction taught by Bartels. Furthermore, the results are predictable because Liu teaches that their methods are compatible with making A to G mutations (paragraph 354).
Furthermore, the D341G mutation is obvious (see rejection of claim 1 for discussion of D341G and its obviousness, incorporated herein).
Response to Arguments
As an initial matter, and for the sake of clarifying the present amendments for the record, the Applicant has amended the independent claims, where the amendments now draw the claims to substitutions of the SERPINA1 gene to render D341G and E342E substitutions, relative to SEQ ID NO: 296 as recited in claim 1. Note that the “E342E” substitution corresponds to a substitution where the pathogenic “K” at 342 is simply reverted back to the wildtype “E” at this residue. This variant was not previously recited, thus, the amendments required new consideration and searches which prompted a new 103 rejection as discussed above. Previous arguments addressing the cited art in the 103 rejection were directed at claim limitations not previously recited in the claims (see office action mailed 11/05/2024 and remarks filed 2/04/2025). Briefly, the Applicant had previously claimed an embodiment where the pathogenic allele was mutated to a non-conservative mutation at position 342. In the present claim language, the pathogenic allele residue 342 has simply been reverted back to its original wildtype form, which is obvious given the teachings of the prior art because this pathogenic allele site (i.e., E342K) was already known as well as methods of targeting genes to correct them (see 103 rejection above).
Furthermore, converting the non-pathogenic residue 341 does not appear to have an overall unpredictable effect on the protein. To elaborate upon this point further, attention is directed to the results of the present substitution, as shown in Figure 3. Figure 3 is partially reproduced below:
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As shown above, Figure 3B shows that mutation of D341G is comparable to wildtype levels of secretion, and are improved compared with the known pathogenic E342K allelic variant. However, this result is not unexpected or surprising because the D341G mutation comprises a wildtype 342 position, and there is therefore no reason to believe that such a protein would be affected by such a mutation, as position 341 is not pathogenic. This position is corroborated further by Figure 3C (above). Figure 3C depicts an assay testing the ability of the A1AT variants to inhibit elastase, where wildtype/normal forms of the protein normally function to inhibit elastase. As seen in Figure 3C, the pathogenic E342K allele does not inhibit elastase, as expected, where the wildtype/regular form of the protein does inhibit elastase. The D341G mutation, which comprises a wildtype/normal 342 residue, also functions as an elastase inhibitor, although with slightly less efficiency compared with WT as evidenced by an increased concentration of the D341G variant required to inhibit elastase activity compared with the wildtype/normal variant. In other words, the A1AT variant which is rendered in the method of claim 1 is the D341G variant, where the pathogenic residue at position 342 is wildtype. Reverting the pathogenic allele to wildtype appears to be sufficient to restore elastase function of the protein, where the D341G mutation simply appears to render a protein that is comparable to or slightly less efficient than the wildtype form. This protein variant result is not surprising, as the 341 position is not a pathogenic mutation. Hence, the “restored” elastane activity of the D341 variant can not be decoupled from the reversion of the pathogenic 342 allele to its wildtype state, which has the same effect of demonstrating elastase activity.
The Applicant argues that their amendments are sufficient to overcome the 112(a) rejection. This argument is persuasive, and the 112(a) rejection is withdrawn. However, the Applicant’s amendment render the claims obvious in view of the new search and 103 rejection, as described above.
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 DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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