Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
Election/Restrictions
Applicant’s election without traverse of species 1 and 2 in the reply filed on 09/02/2025 is acknowledged. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicants election of the following species in the response filed 09/02/2025 is as follows:
1) An edited Hb-beta polypeptide (claim 1); Applicant elects species (ii) as recited in claim 1.
2) A guide RNA sequence (claim 9); Applicant elects species (i) as recited in claim 9.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/GB2019/052696, filed 09/25/2019.
Applicant’s claim for the benefit of a prior-filed foreign priority document GB1815670.3, filed on 09/26/2018, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. A certified copy of the prior-filed foreign priority document GB1815670.3 is also acknowledged.
Thus, the earliest possible priority for the instant application is 09/26/2018.
Claims Status
Claims 5-6, 10-11, 16-17 and 19 are canceled and claims 1-4, 7-9, 12-15, and 18 have been considered on the merits. All arguments have been considered.
Withdrawn Objections & Rejections
Applicant's response filed 01/27/2026 has been considered. Rejections and/or objections not reiterated from the previous Office action mailed 10/27/2025 are hereby withdrawn.
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Responses to the pertinent Arguments filed 01/27/2026 can be found below the rejections.
Claim Rejections - 35 USC § 103 (Maintained)
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.
Claims 1-4, 7-9, 12-15 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al. (Protein & Cell (2017) 8:11;811-822, as cited in the IDS filed 7/13/2021), Hoban et al (Blood (2015)125:17;1-8, as cited in the IDS filed 7/13/2021), Guadelli et al (Nature (2017)551:23(464-487, as cited in the IDS filed 7/13/2021), Viprakasit et al (Hemoglobin (2002)26;1-10), Urnov et al (US 7888121B1 2011) and Leenay et al (J Mol Biol (2017)429:2;1-25).
Regarding claims 1-3 and 18: Claim 1 (ii) recites the first non-wild-type codon corresponds to codon 7 in Seq ID NO:1. Figure 2 of the instant specification identifies codon 7 as the first “GAG” in the “GAGGAG” repeat.
Liang teach β-Thalassemia is caused by mutation in the HBB gene (abstract). Liang further teach a method for editing the HBB gene comprising contacting a nucleic acid molecule comprising a mutant hemoglobin B gene with the base editor BE3 to replace the mutant base (G-28) with the wildtype base (A-28). (p812 col2 ¶2 and title). Liang also teach incubating the nucleic acid molecule comprising the mutant HBB gene, the base editor, and the gRNA under conditions such that the gRNA targets the base editor to the nucleotide sequence of the first non-wild-type codon of the mutant HBB gene to a second codon within a human cell (p814 col2 ¶2).
Liang do not teach the mutant HBB gene encodes a mutant hemoglobin-β polypeptide. Liang do not teach the first non-wild-type codon corresponds to codon 7 in Seq ID NO:1, wherein the wild-type codon at this position is GAG, the first non-wild-type codon is GTG and the second non-wildtype codon is GCG. Liang do not teach the base editor is an adenine base editor.
Hoban teach sickle cell disease is characterized by a single point mutation in the seventh codon of the β-globin gene (which corresponds to the sixth codon of the instant claim), and that site-specific correction of the sickle mutation in hematopoietic stem cells would allow for permanent production of normal red blood cells (abstract). Hoban teach the edited cells are donated from donors with sickle cell disease (p2 col1 ¶3).
Hoban teach a first non-wild-type codon that corresponds to codon 7 in Seq ID No:1 is the mutated seventh codon “GTG” which is a sickle mutation (Figure 1a,c). Hoban further teach replacing the mutated seventh codon “GTG” with a corrected nucleotide sequence (Figure 1a,c).
Hoban do not teach a second non-wild-type codon is “GCG”. Hoban do not teach the base editor is an adenine base editor.
Guadelli teach adenine base editors (ABE) that convert AT to GC base pairs in genomic DNA in human cells (p464 col2 ¶1). Guadelli disclose sgRNA that directs the ABE to the γ-globin gene promoter to edit a specific base at a specific position (-198T to -198C) (p470 col1 ¶2).
Viprakasit teach that a person homozygous for “GCG” at codon six of HBB (which corresponds to codon 7 of the instant claim) is hematologically normal (abstract).
It is noted that codon numbering of Viprakasit varies by 1 number compared to numbering in the instant specification, but that codon 7 of Viprakasit encodes the first “GAG” of the “GAGGAG” of the HBB sequence and thus reads on a codon that corresponds to codon 7 in Seq ID NO:1.
It would have been obvious to one of ordinary skill in the art to adapt the methods of Liang drawn to a method of modifying a mutant HBB gene comprising contacting a first-non-wild-type codon with a base editor by contacting a mutant HBB gene wherein the first non-wild-type codon is “GTG”, as taught by Hoban, wherein the base editor is an adenine base editor, as taught by Guadelli, and wherein the second non-wild-type codon is ”GCG” as taught by Viprakasit.
One of ordinary skill in the art would have been motivated to modify the method taught by Liang with the teachings of Hoban, Guadelli and Viprakasit because Viprakasit teach the non-wild-type codon “GCG” does not produce a disease phenotype and thus modification of the HBB gene represents a potential cure of the disease causing mutation of the “GTG” codon 6 mutation taught by Hoban.
Furthermore, one would be motivated to use an adenine base editor to change the “GTG” codon to the “GCG” as taught by the combination of Hoban and Viprakasit because Guadelli teach adenine base editors mediate the conversion of “A·T” to “G·C” in genomic DNA with far fewer undesired products compared with standard genome editing methods, and the GTG to GCG change taught by the combination of Hoban and Viprakasit would be mediated by an adenine base editor.
One would have had a reasonable expectation of success because Liang teach base editing can specifically alter a single base in the HBB gene to correct a disease causing mutation and one of ordinary skill in the art would understand that an adenine base editor which efficiently converts “A·T” to “G·C” in a wide range of target genomic loci in in human cells efficiently and with a very high degree of product purity would have a reasonable expectation of success (p464 col2 ¶2).
Regarding claim 4: The claim refers to Seq ID NO:2. The instant specification teaches Seq ID NO:2 is the wild-type HBB amino acid sequence (p9 ln25-30).
The teachings of Liang are discussed supra. Liang also teach a mutant HBB allele with mutations occurring in promoter region. Therefore the amino acid sequence of the HBB allele would be 100% identical to the amino acid sequence of the wild-type human HBB polypeptide (SEQ ID NO: 2).
Liang do not teach the mutant HBB encodes an amino acid sequence with 90-99.5% sequence identity to SEQ ID NO: 2.
Hoban teach a first non-wild-type codon that corresponds to codon 7 in Seq ID No:1, the mutated seventh codon “GTG” which is a sickle mutation (Figure 1a,c). A nucleotide sequence encoding an amino acid sequence that is identical to wild type HBB (Seq ID No: 2), except for a single amino acid change (such as the mutated seventh codon taught by Hoban), would encode an amino acid sequence within the range of 90-99.5% sequence identity to Seq ID NO:2.
The mutation taught by Hoban is a point mutation, and thus it would be obvious to select a mutant HBB allele that encodes a highly similar amino acid sequences compared to the wild-type sequence of SEQ ID NO: 2 such as that taught by Hoban. Specifically, Hoban teach and HBB amino acid sequence with 99.32% sequence identity with Seq ID NO:2.
MPEP 2131.03 reads “when, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art”.
It would have been obvious to one of ordinary skill in the art to adapt the methods of Liang drawn to producing an edited HBB gene by using an HBB gene which encodes an amino acid sequence having 90-99.5% sequence identity with wild type HBB (Seq ID NO: 2).
Hoban discloses a point mutation which is causative for sickle cell disease and the encoded amino acid shares 99.32% identity with Seq ID NO:2.
Accordingly, one of ordinary skill in the art would have been motivated to modify the teaching of Liang, which targets an HBB gene encoding a nucleic acid sequence with 100% identity with Seq ID NO:2 by targeting an HBB gene which encodes an amino acid sequence with 90-99.5% sequence identity to seq ID NO: 2 to for the purposes of correcting disease causative mutations which occur in the coding sequence of the HBB gene, such as that taught by Hoban which is causative for sickle cell disease.
One would have had a reasonable expectation of success because Liang discloses successful gene editing of the HBB gene and one of ordinary skill in the art would understand that additional nucleotide positions in the HBB gene could also be targeted with the disclosed nucleotide editing system.
Regarding claim 7: The teachings of Liang are discussed supra. Liang also teach the base editor BE2 comprises dCas9, which one of ordinary skill in the art would understand represents an impaired Cas9 mutant (p811 col2 ¶2).
Regarding claim 8: The teachings of Liang are discussed supra. Liang do not teach the base editor is an adenine deaminating editor.
Gaudelli teach a base editor is an adenosine deaminase (p471 col1 ¶2).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Liang drawn to a process for producing a modified nucleic acid molecule by using an adenine deaminating editor as taught by Guadelli. Guadelli discloses a base editor that is an adenosine deaminase and successfully edits genomic DNA at a specific nucleic acid residue from T to C (p470 col1 ¶2).
Accordingly, one of ordinary skill in the art would have been motivated to modify the method as taught by Liang to for the purposes of modifying a specific genomic residue to change a A•T to G•C.
One would have had a reasonable expectation of success because Guadelli discloses the adenosine deaminase base editor successfully edits genomic DNA to change a A•T to G•C.
Regarding claim 9: The teachings of Liang are discussed supra. Liang also teach gRNA for targeting HBB-28 (A>G) (abstract).
Liang do not teach the gRNA for editing the nucleotide sequence of HBB at the codon which corresponds to codon 7 in Seq ID NO: 1 is an 18-22 nucleotide guide RNA which is complementary to a nucleotide sequence located in Seq ID NO:15 wherein the codon which corresponds to the wild-type complement of codon 7 in Seq ID NO:1 is replaced by CAC.
Urnov teach methods and compositions for targeted alteration of a genomic sequence (abstract). Urnov teach a target site for the human β-globin gene (HBB) with a CAC sequence that corresponds to the wild-type complement of codon 7 in Seq ID No:1, which is sequence 181 of Urnov. Sequence 181 of Urnov has 100% identity to seq ID NO:15 of the instant application (p87).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Liang drawn to a method to edit the HBB gene using a base editor by using a gRNA to the target site as disclosed by Urnov. Urnov teach the A-T substitution causes sickle cell disease.
Accordingly, one of ordinary skill in the art would have been motivated to modify the method as taught by Liang by using a gRNA to target the sequence disclosed by Urnov to for the purposes of editing the sickle cell causing mutation in the HBB gene.
One would have had a reasonable expectation of success because Liang discloses single nucleotide changes in HBB genomic sequences and Urnov teach a target that is the well-known cause of sickle cells disease.
Regarding claim 12, 14-15: The teachings of Liang are discussed supra. Liang also teach obtaining a sample of cells from a subject wherein the cells comprise nucleic acid molecules comprising mutant HBB genes; Liang teach isolating and culturing skin fibroblast cells from a homozygous mutant patient (p814 col1 ¶2). Liang also disclose high repairing efficiency in human hematopoietic stem cells, such as with the disclosed precision base editors, will lead to new therapeutics for β-thalassemia patients (p818 col1 ¶3).
Liang do not teach introducing a population of hematopoietic stem cells comprising modified nucleic acids comprising edited HBB genes into the same or related subjects.
Wen teach obtaining a sample of hematopoietic stem cells (HSPCs) from the peripheral blood of a patient (human subject) with sickle cell disease (p7 col2 ¶1). One of ordinary skill in the art would understand that cells from a patient with sickle cell disease comprise a mutant HBB gene.
Wen teach using CRISPR/Cas9 targeted with sgRNA specifically targeting the V6G mutation which causes sickle cell disease (and corresponds to the GTG non-wild type codon 7 of Seq ID NO: 1) and successfully editing the HSPCs (p5 col1 ¶2). Wen teach autologous transplantation of the genome edited HSPCs represent a cure for sickle cell disease (p7 col1 ¶1). Autologous transplantation reads on performing the process on hematopoietic cells which have been obtained from a first subject and introducing a population of hematopoietic stem cells comprising edited HBB genes into the same subject.
Regarding claim 13: The teachings of Liang are discussed supra. Liang do not teach modifying the nucleotide sequence of one or more PAM site in the vicinity of the first non-wild-type codon.
Leenay teach Cas effector proteins rely on protospacer-adjacent motifs (PAM sequences) as the first stem in target recognition, and PAM sequences are known to vary between systems (abstract). Figure 3 teaches PAM orientation is different for different types of CRISPR-Cas systems (p20). Table 1 teaches consensus PAM sequences for some CRISPR-Cas systems (p25).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Liang drawn to a method of editing an HBB gene by modifying the PAM sequence to be optimally efficient with the chosen CRISPR-Cas system because Leenay discloses PAM sequences and orientation differ depending on the chosen CRISPR-Cas system.
Accordingly, one of ordinary skill in the art would have been motivated to modify the method as taught by Liang to optimize the PAM sequence with the teachings of Leenay for the purposes of developing an effective CRISPR-Cas system with the Cas targeting protein required by the base editing system.
One would have had a reasonable expectation of success because Leenay discloses PAM consensus sequences that represent the most active PAM sequences and one of ordinary skill in the art would understand that the protein editor must be guided by the appropriate PAM sequence to comprise a functional DNA targeting system.
Response to Arguments
The responses are directed to the Arguments filed 01/27/2026.
Regarding Arguments directed to 35 USC § 103:
Applicant's arguments filed on 01/27/2026 have been fully considered and they are not persuasive.
Applicant’s arguments focus on the combination of Liang, Hoban, Guadelli and Viprakasit, for which Applicant submits the approaches are incompatible, that there is no rational for determining how to combine the prior art, and that the motivation for modification of the primary reference Liang amounts to “pure speculation”. As discussed below, the arguments are considered unpersuasive and the rejection is maintained.
The rejection in the present action is based upon the facts that:
1) Base editing methods to edit the HBB gene were known in the prior art (Liang).
2) The disease causing codon “GTG” of the HBB gene (which corresponds to codon 7 of Seq ID NO: 7 of the instant disclosure) was known in the prior art (Hoban).
3) A non-disease causing variant of the HBB gene, codon “GCG” (which corresponds to codon 7 of Seq ID NO: 7) was known in the prior art (Viprakasit).
3) Tools to allow modification of the editing a disease causing codon to a non-disease causing codon were known in the art (adenine base editor as taught by Guadelli).
Applicant submits the combination of references rely on hindsight reasoning and lacks motivation for combination.
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 submits there is no motivation for the combination of the references as recited in the rejection over claim 1, that the references comprise incompatible approaches and that the proposed modification of Liang is speculation because the rational “represents a potential cure” is speculative.
In regards to motivation, Applicant focuses on a single phrase of the prior office action regarding a potential cure. Applicant suggests the modification of Liang amounts to pure speculation.
While one may reasonably construe that the modification of a gene from a disease causing variant to a non-disease causing variant does represent a potential cure for the disease, a cure for a disease is not the test being applied to demonstrate obviousness.
The test being applied to demonstrate obviousness is would one of ordinary skill in the art be motivated to repair a genetic defect of HBB by modifying an HBB variant which is known to cause disease (GTG) by modifying the HBB sequence to generate a variant which is known to not cause disease (GCG).
It is self-evident that one of ordinary skill in the art would be motivated to repair a disease causing mutation by changing the nucleic acid sequence of the disease causing variant to the sequence of a variant that is known to not cause disease.
Regarding Applicants allegation that the combined art comprises incompatible approaches, the argument is akin to the bodily incorporation argument in which all of the features of a secondary reference are fully incorporated into the primary reference.
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
The art is relied upon and cited for specific teachings such as the specific sequence of a disease causing HBB variant, the specific sequence of a non-disease causing HBB variant, and gene editing tools which one of ordinary skill in the art would have recognized could have been used to edit the HBB gene.
Applicant argues the relied upon art do not teach specific features of the claimed invention. For example “This is not all Liang/Hoban do not teach”, “Guadelli do not teach” (p8, 9, 10 of Arguments).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that Viprakasit was published 17 years before the filing date of the instant application and thus the disclosure was essentially unusable, in a therapeutic sense, because the disclosures were forgotten; they lay buried under the mountains of subsequent scientific literature.
In response to applicant's argument based upon the age of the references, contentions that the reference is old are not impressive absent a showing that the art tried and failed to solve the same problem notwithstanding its presumed knowledge of the references. See In re Wright, 569 F.2d 1124, 193 USPQ 332 (CCPA 1977).
Applicant argues that if a skilled person would have considered the relied upon references, there is still a considerable gap between the combined teachings of the references and the present method. This argument fail to comply with 37 CFR 1.111(b) because they amount to a general allegation without specifically pointing out how the language of the claims patentably distinguishes them from the references. If Applicant were to clearly point out the considerable gap between the combined teachings of the art and the present method, the Office could consider the merits of the argument.
Applicant notes Liang is modified by four references. The relevance of this statement is not clear because reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 ANDREA LYNNE MORRIS SPENCER whose telephone number is (571)272-3328. The examiner can normally be reached Monday-Friday 9:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
Prosecution Insights