DETAILED ACTION
All objections and rejections raised in prior Office Actions are withdrawn unless restated below.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/03/2026 has been entered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 5-6, 9-12 and 14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “a nucleic acid sequence encoding at least one MECP2 gene comprising a mutation.” “A mutation,” as recited is understood to be a base within a sequence of MECP2 gene. What is considered to be a mutated base or a non-mutated or wild-type base or sequence is unclear regarding which base pairs thereof are “mutated” in the absence of a reference of what constitutes an unmutated or wild-type base pair. For example, a naturally-occurring sequence apparently can be considered to be mutated as set forth on page 9 of the specification (“for example, a wild type naturally occurring nucleic acid sequence or a mutated naturally occurring sequence.”).
Reciting “a nucleic acid sequence encoding at least one MECP2 gene comprising a mutation” implies that there are MECP2 gene nucleic acid sequences lacking a mutated base that would fall outside of this claim limitation. “When a subjective term is used in the claim, the examiner should determine whether the specification supplies some objective standard for measuring the scope of the term. Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite.” MPEP 2173.05(b)(IV). Here, there is no objective standard to determine what constitutes a mutated MECP2 to a wild type MECP2 gene, particularly since naturally-occurring sequences . Similarly, there is no objective basis to determine when such mutated base pair is reverted to a wild type base pair, which is arbitrary and subjective for the same reasons that a mutated base pair is. With no ability to determine if a nucleic acid sequence does or does not have a mutated base pair, an ordinarily skilled artisan cannot understand how to avoid infringement. This rejection can be overcome removing “mutation” from the claim and reciting a method wherein one base is changed to another base within the MECP2 gene.
It is noted that claims 25-34 are not included in this rejection, since claim 25 facially indicates that the mutation is tied into being causative for Rett syndrome.
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 25-34 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
An “analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.” MPEP 2164.01. “A conclusion of lack of enablement means that . . . the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention [i.e. commensurate scope] without undue experimentation.” In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); MPEP 2164.01.
In In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988), several factors implicated in determination of whether a disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” are identified. These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). No single factor is independently determinative of enablement; rather “[i]t is improper to conclude that a disclosure is not enabling based on an analysis of only one of the above factors while ignoring one or more of the others.” MPEP 2164.01. Likewise, all factors may not be relevant to the enablement analysis of any individual claim.
“According to In re Bowen, 492 F.2d 859, 862-63, 181 USPQ 48, 51 (CCPA 1974), the minimal requirement is for the examiner to give reasons explaining the uncertainty of the enablement. This standard is applicable even when there is no evidence in the record of operability without undue experimentation beyond the disclosed embodiments.” See also In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995); MPEP 2164.04.
Claim Scope
As an initial matter, the scope of claim 25 and claims depending therefrom will be discussed. Claim 25 recites a method of in parallel administering a fusion protein for gene editing (consequence of cytidine deaminase activity) to a patient and contacting the same fusion protein with a separate nucleic acid sequence apart from the patient wherein there is no interaction between the recited patient and the recited nucleic acid sequence. Further, “administering said fusion protein to said patient” is understood as requiring that the protein is physically administered to the patient and not a nucleic acid, viral vector nor a nucleic acid in a lipid particle being administered to the patient. A flow diagram appears below summarizing the method of claim 25 and more specifically further dependent claims 28-29:
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That is, claim 28 recites “further providing a biological sample comprising said nucleic acid sequence.” A biological sample is not understood to be the patient recited in claim 25. Since claim 25 already recites providing the patient, the biological sample recited in claim 28 has to be a different structure than the patient in order for claim 28 to be further limiting within the meaning of 35 U.S.C. 112(d). Further, a biological sample is understood to not be a complete organism; for example, a tissue sample having DNA (i.e. nucleic acid) therein. While it may be possible for provision of a patient having Rett syndrome to simultaneously satisfy the claim limitations of “providing: i) a patient exhibiting at least one symptom of Rett syndrome; [and] ii) a nucleic acid sequence endowing at least one MECP2 gene comprising a mutation” (such nucleic acid sequence being part of the genome of the patient), this interpretation is prevented by 1) claim 25 reciting separate administering and contacting steps for the patient and the nucleic acid sequence, and 2) claim 28 explicitly reciting that nucleic acid sequence is a biological sample and not the patient.
As such, claim 25 requires the fusion protein to act on two separate structures in two separate administering and contacting steps as recited: 1) a patient, and 2) a nucleic acid sequence that can be within a non-patient biological sample, wherein the nucleic acid sequence is not present in the patient.
To emphasize, the above is not a discussion that a possible embodiment of claim 25 is that the recited nucleic acid sequence is not part of the genome of a living patient, but rather that claim 25 requires in all possible embodiments that the recited nucleic acid be a structure apart from and not present in the genome of the patient wherein claim 28 further explicitly requires the nucleic acid sequence to be present in a biological sample that is not the patient.
Further, claims 25 requires that reverting the nucleic acid sequence to a wild type MECP2 gene results in “said at least one symptom of Rett syndrome is reduced,” wherein the antecedent basis for “said at least one symptom of Rett syndrome” is the recited patient having Rett syndrome.
In further review of above, an embodiment of the claims is providing a patient and administering a fusion protein (and not an encoding nucleic acid) as recited to the patient. Parallel to the administration of a fusion protein in to the patient, a nucleic acid sequence in a biological sample is provided in a plastic tube, such nucleic acid sequence having a mutated MECP2 gene. The nucleic acid sequence in the plastic tube is contacted with the fusion protein and the nucleic acid sequence reverted to a wild-type MECP2 gene, upon which time at least one symptom of Rett syndrome of the patient is reduced via some unrecited and undescribed mechanism.
Wands factors (A)-(C)
In view of the above, the claims recite correction of a nucleic acid sequence having a MECP2 gene with a mutation and reverting the MECP2 gene to a wild-type gene, wherein the nucleic acid is not present within a patient nor any other living organism. Nevertheless, modification of such nucleic acid sequence that is not part of the genome of a patient results in reduction of Rett symptoms in the patient through an unrecited mechanism and having no corresponding theoretical explanation in the specification.
Porto et al. (Base editing: advances and therapeutic opportunities, Nature Rev. 18, 2020, 839-59), page 839, left col., states: “To be used as a therapeutic, a genome editing tool must demonstrate high on-target efficiency and minimal harmful or undesired off-target edits, and be deliverable to the organ(s) of interest.”
As reviewed above, the rejected claims recite use of a genome editing tool (i.e. the recited fusion protein) wherein the editing or base change that occurs is not within an “organ of interest” or within a patient at all but is expressly within a biological sample, as discussed above, but nevertheless requires improvement of Rett symptoms in a patient. Porto evidences the state of the prior art does not support that it is possible to treat a genetic disease by modification of a nucleic acid sequence that is extracorporeal to the patient to be treated.
In the event the claims are intended to require or are amended to require that a MECP2 gene that is part of the genome of the patient to be reverted to a wild-type sequence by administration of a fusion protein as to reduce a symptom of Rett syndrome, the following is noted:
The specification, page 23, provides “One challenge with the current Cas9 base editing system is the necessity to have a complementary PAM a the correct position and on the appropriate DNA strand to target the activity of the cytosine or adenosine base editors to precise genomic positions that are targeted for conversion.” “In one embodiment, the present invention contemplates a Cas9-base editing platform that has a much broader targeting range for PAM recognition than the standard SpyCas9 systems. For example the Cas9-base editing platform hybridizes proximate to a single G (NGN or NNG) rather than two Gs as in traditional NGG SpyCas9 Pam motifs.” Specification, page 24.
While there are only four nucleotide bases, not all Rett-causing mutations will occur within a targeting range of a NGN or NNG PAM sequence including any mutated base pair that is endogenously present in a patient exhibiting at least one symptom of a genetic disease being Rett syndrome. Regarding Rett syndrome, Lyst et al. (Rett syndrome: a complex disorder with simple roots, Nature Rev. Genetics 16, 2015, 261-74), Figure 1, evidences that many mutations are associated with Rett syndrome wherein it is unpredictable regarding which mutations may successfully be reverted by the fusion protein recited.
Coorey et al. (Gene editing and Rett syndrome, CRISPR J 5, 2022, 490-99, prepublication cited) is not prior art but evidences the skill in the art at the time of filing. Coorey, page 4, provides:
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As such, the state of the prior art is that it is 1) difficult to treat Rett syndrome by any type of gene therapy due to complexity of MECP2 expression in the brain and, 2) difficulty in delivering a therapeutic payload through the blood brain barrier.
Wands factors (D)-(H)
Since Proto evidences that treatment of a genetic disorder such as Rett requires actual delivery of the recited base-editing fusion protein to an appropriate organ of the patient to be treated, it is unpredictable even in view of a high level of skill in the art (e.g. an individual with a doctoral degree) to practice an embodiment of the rejected claims wherein a symptom of Rett syndrome is reduced by modifying a nucleic acid sequence that is extracorporeal to the patient. The specification has no working examples of reducing a symptom of Rett syndrome by modifying a nucleic acid that is not part of the genome of the patient.
Stated in other words, it is not technically possible to edit a MECP2 gene sequence that is extracorporeal to a patient to cause a reduction in a Rett symptom in the patient and attempting to achieve such a result requires unguided experimentation that is not routine in the art.
In the event the claims are intended to require or are amended to require that a MECP2 gene that is part of the genome of the patient to be reverted to a wild-type sequence by administration of a fusion protein as to reduce a symptom of Rett syndrome, the following is noted:
Porto, page 853, left col.:
Although the sheer number of base editor variants and
delivery strategies may seem inordinate, each disease
target will require a unique combination of base editor,
gRNA or ASO and delivery method. Specifically, the requisite
level of on-target efficiency to afford a phenotypic
response will vary drastically according to the disease.
. . . The disease will also dictate
to which tissue or organ the base editor must be delivered,
which in turn will determine what delivery method
must be used. The genetic diversity of humans adds yet
another layer of required customization: it is possible
that two individuals who require correction of the same
SNV will need different gRNA sequences.
There is unpredictability in the ability to deliver such a base editor fusion protein to a subject endogenously having a mutated base pair to affect any level of reversion of mutated MECP2 gene to a wild-type MECP2 gene. The specification does not demonstrate any ability to utilize any fusion protein disclosed to modify a MCEP2 gene even in an isolated cell nevertheless in a living patient as to reduce a symptom of Rett syndrome.
Pages 31-32 of the specification report an embodiment wherein activity of adenine base editors were validated with an mCherry reporter line wherein a shift form no signal to a red signal (from GFP) occurs subsequent to modification of a codon from tag to cag. The specification does not make clear what the target polynucleotide of the mCherry encodes other than GFP including if any sequence relevant to Rett disease is present. Regardless, while such a mCherry assay shows the functionality to cleave a designed sequence, the same does not demonstrate an ability to perform a nucleotide base reversion potentially in vivo wherein a mutated base pair and its surrounding sequence are not preselected. As discussed above particularly by Porto, actual treatment of a genetic disease or reduction of a symptom thereof, or even performing an in vivo base change without necessarily achieving a beneficial result, presents several technical challenges and is unpredictable. In view of the specification not provided any ability to perform an in vivo base modification in any in vivo model, an ordinarily skilled artisan would have to undertake open-ended experimentation in kind and quantity to successfully deliver a fusion protein as a base editor as recited, successfully revert a mutated base to a “wild type” base pair, and at a tissue local and efficiency that will actually reduce a symptom for Rett wherein Coorey indicates that such a change in a MECP2 gene will have to occur in the brain of a patient in order to treat a symptom of Rett. Regardless of an apparent high degree of skill in the art, such a degree of experimentation is not routine in the art and is therefore undue. That is, at least Porto demonstrates the high skill in the art but nevertheless states that a large amount of customization, which cannot be predicted without experimentation, is required to address reversion of any specific base mutation.
It is noted that the description of the Figures of the specification describe some examples of base editing performed in cells, but with minimal experimental explanation. For example, Figures 7-11 (pages 17-18) describes some sort of editing of a cell but apparently directed towards a “KANK3 locus” that has no clear relationship to a MECP2 gene.
As reviewed above, the state of the art at time of filing is that it is 1) difficult to treat Rett syndrome by any type of gene therapy due to complexity of MECP2 expression in the brain and, 2) difficult to deliver a therapeutic payload through the blood brain barrier. The specification provides no guidance for overcoming theses technical obstacles such that in order to practice the claims to achieve reduction of a Rett symptom requires an ordinarily skilled artisan to engage in unguided experimentation to 1) achieve MECP2 expression that may alleviate a symptom of Rett syndrome, and 2) deliver the recited fusion protein across the blood brain barrier, which is not routine in the art. In particular, it is noted that Coorey discusses the use of adenovirus vectors to affect a gene-based therapy, which are well understood in the art to deliver nucleic acids to target cells where they may then be expressed. Coorey, page 14 (Whilst AAV9 is currently the gold standard of virus-mediated delivery for targeting the CNS by systemic injection, the efficiency of transduction of neural cells is suboptimal and delivery mechanisms still need further advancement.). For example, Porto, Fig. 4, illustrates how an adenovirus can be used to deliver a nucleic acid encoding a base editor that is then produced by a cell by translation. However, claim 25 recites providing a fusion protein and does not recite providing a nucleic acid encoding a fusion protein, wherein the fusion protein and not a nucleic acid encoding the fusion protein is administered to a patient. There is no discussion in the specification nor any apparent discussion anywhere in the art of record of how a fusion protein originating from outside the patient would reach brain tissues and enter a brain cell as to edit the genome thereof including an endogenous MECP2 gene. Solving such a technical problem without a large amount of guidance (that has not been provided) is not routine in the art even for very highly skilled artisans as evidenced by at least Porto and Coorey.
As such, the Wands factors reviewed above all weight towards non-enablement for the rejected claims.
Response to arguments
Applicant argues:
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Claim 1 does not recite nor involve “hereditary material.” An embodiment of claim 1 is a nucleic acid sequence produced by solid state synthesis wherein practice of the claims does not require any living system having any “hereditary material.” That is, an artificially produced nucleic acid sequence, particularly when incorporated into a vector, is a “gene” even when not part of the heritable genetic material of a cell, or not located in a cell at all. It is noted that any artificially produced polynucleotide, mutated or not, is “permanent” [i.e. the sequence thereof will not spontaneously change] such that a state of being “permanent” cannot differentiate a nucleic acid sequence of an artificial polynucleotide from another sequence that is arbitrarily considered to be non-mutated. As such, there has to be some objective basis to differentiate a mutated sequence from a non-mutated sequence, which is not provided. The mutations recited in the claims are not limited to the specific mutations illustrated in the specification, but encompass any mutation. The rejection may potentially be overcome by reciting a more generic method of modifying a nucleic sequence of MECP2 without reference to mutations, or by reciting pathogenic mutations.
Applicant argues:
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The new claims are noted and addressed above.
Examiner comment regarding prior art
In addition to Fauser et al. (U.S. 2020/0063114 A1) and Bryson (WO 2019/217944 A1) discussed in detail in a prior Office Action, the closest prior art uncovered includes:
Bolukbasi et al. (Nature Comm. 9, 2018, 4856) (see IDS 7/28/22), abstract: Dual-nuclease Cas9-Cas9 chimeras have distinct advantages over monomeric Cas9s including higher target site activity and the generation of predictable precise deletion products between their target sites.
Bryson is considered to be the closest prior art to the claims teaching dCas9 fused to a deaminase for application to Rett mutations. Bryson, para. [0043].
Bolukbasi indicates that application of two Cas9 domains as a Cas9 chimera can have higher specificity than a single Cas9 domain. However, the structure taught by Bolukbasi is different as claimed wherein Bolukbasi teaches a fully active Cas9 (not a nickase) fused to an orthogonal dCas9. Fauser does not suggest two orthogonal Cas9 domains but emphasizes a ZFP as fused to a nickase Cas9 and a deaminase. Without benefit of applicant’s disclosure, there is not deemed sufficient motivation to 1) modify embodiment of Bolukbasi to be a nickase rather than a full nuclease, and 2) substitute the same into embodiments of Fauser to replace the ZFP and cas9 nickase domains taught therein.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TODD M EPSTEIN whose telephone number is (571)272-5141. The examiner can normally be reached Mon-Fri 9:00a-5:30p.
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
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