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 .
Status of Claims
This action is written in response to applicant’s correspondence receive on 09 December 2024. Claims 1, 2, 5, 8, 9, 13, 14, 18, 19, 22, 25, 26, 30, 31, 36, 37, 39, 41, 43, and 44 are currently pending and examined herein.
Priority
The instant application claims priority based on a US Provisional Application No. 63/154,432 filed on February 26, 2021. The provisional application describes claims 1, 2, and 13 ([0006]), claims 5 and 8 ([0007]), claim 14 ([0009], claims 18, 19, and 30[0010]), claim 22 and 25 ([0011] and [0015]), claim 31 ([0013]), claims 36, 39, and 41 ([0014]), claims 43 and 44 ([0015]). Accordingly, the effective filling dates of instant claims 1, 2, 5, 8, 13, 14, 18, 19, 22, 25, 30, 31, 36, 39, 41, 43, and 44 is February 26, 2021.
Support for the recitation of “and the polynucleotide further comprises a gamma-Synuclein promoter” is described in [0008], [0012], and [0014]. However, support for the recitation “and the polynucleotide further comprises a gamma-Synuclein promoter, a Synapsin 1 promoter, a Neurofilament Heavy promoter, or a Thy-1 cell surface antigen promoter” as recited in instant claims 9, 26, and 37 could not be found in US Provisional Application No. 63/154,432. Therefore, instant claims 9, 26, and 37 are not afforded the effective filling date of February 26, 2021.
The instant application also claims priority based on a US Provisional Application No. 63/177,230 filed on April 20, 2021. The provisional application provides support for the recitation “and the polynucleotide further comprises a gamma-Synuclein promoter, a Synapsin 1 promoter, a Neurofilament Heavy promoter, or a Thy-1 cell surface antigen promoter” as recited in instant claims 9 ([0008]), 26 ([0012]), and 37 ([0014]). Accordingly, the effective filling date of instant claims 9, 26, and 37 is April 20, 2021.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete. The Sequence Listing, in ASCII text file is designated H2745154.txt and is 119406 B, while the Sequence listing disclosed in the specification’s incorporation by reference statement is “H2257236.txt and is 119.4 KB in size”([0003]). The names of the ASCII text file do not match and the size of the ASCII text file is not in bytes.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: The specification teaches “FIGs. 55A and 5F” ([0141]) which contains a typo error because there is no FIG. 55A.
Appropriate correction is required.
Claim Objections
Claims 14 and 31 are objected to because of the following informalities: Claims 14 and 31 recite “retinal ganglion call axons” which contains spelling errors; therefore, it should read as “retinal ganglion cell axons”. Appropriate correction is required.
Claim Rejections - 35 USC § 112 - Enablement
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 1, 2, 5, 9, 13, and 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of decreasing degeneration of retinal ganglion cells in a subject comprising administering a composition comprising a CaMKIIα comprising a T286D substitution and/or a CaMKIIβ comprising a T287D substitution, does not reasonably provide enablement for such method wherein the composition comprises a CaMK. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
Claims are directed to a method of decreasing degeneration of retinal ganglion cells in a subject, comprising administering a composition that comprises a calcium-calmodulin dependent kinase (CaMK) or a polynucleotide encoding the CaMK.
Breadth of the Claims
With respect to claim breadth, the standard under 35 U.S.C. § 112(a) entails determining what the claims recite and what claims mean as a whole. The claim merely recites administering to the subject a composition…comprises the CaMK or a polynucleotide encoding the CaMK, which under broadest reasonable interpretation, is interpreted as any administration of any variants of CaMK and any isoforms of CaMK.
Guidance of the Specification
The specification provides working examples with CaMKIIα and CaMKIIβ wild-type and a few variants for each isoform including K42R, K42D, T286A, T286D (T287D for CaMKIIβ), T305A, T305D, T306A, and T306D ([0103]). The specification further teaches enhancing the activity of CaMKII variants indeed decreased degeneration of RGCs from excitotoxic or axonal injuries (FIGs. 3A-3T and FIG. 5F; [0140]-[0142]). In fact, the two constitutively active CaMKIIα T286D and CaMKIIβ T287D variants were most effective in countering excitotoxic or axonal injuries, even at 12 months after injury (FIGs. 6F-6K, and FIG. 6O; [0149]).
The specification does not provide working examples with variants of additional CaMKII isoforms and no working examples with any variants of CaMKI or CaMKIV.
Thus, specific guidance is provided for only a limited scope of the claims, where only specific variants of CaMKIIα and CaMKIIβ isoforms are capable of decreasing degeneration of retinal ganglion cells in a mouse-models when “CaMKII has four isoforms (α, β, γ, and δ) in mammals, with each isoform expressed from a different gene” ([0134]). Despite the specification teaches “CaMKIIα and CaMKIIβ are the two major isoforms highly expressed in the rodent retina” ([0134]), the breadth of the claims encompasses any CaMK, not specific variants of CaMKIIα and CaMKIIβ.
State of the Art
At the time of the filling, the state of the art relating to decreasing degeneration of RGCs or also known as neuroprotection, demonstrated that such method is performed via inhibition of CaMKII instead of the contrary increasing activity of any CaMK in the claimed invention.
Fan et al (Retinal ganglion cell death and neuroprotection: Involvement of the CaMKIIα gene; Molecular Brain Research, 2005, 139:306-316) teaches caspase-3 activation plays a central role in apoptosis as activated caspases kill cells by degrading structural elements and DNA repair enzymes and by indirect activation of chromosomal endonucleases (pg. 314, left column, second paragraph), and that “CaMKII is involved in the activation of caspase-3, but not in the transcription or translation of the proenzyme” (pg. 314, right-column, second paragraph). Fan further teaches although glutamate caused an increase in phosphorylation at Thr286 of CaMKIIα, the presence of an inhibitory peptide AIP blocked this autophosphorylation significantly and completely inhibited CaMKII-mediated phosphorylation (Fig. 8; pg. 312, left-column, second paragraph). Goebel et al (Selective blockade of CaMKII-α inhibits NMDA-induced caspase-3-dependent cell death but does not arrest PARP-1 activation or loss of plasma membrane selectivity in rat retinal neurons; Brain Research, 2009, 1256: 190-204) further confirmed Fan’s teachings where inhibition of CaMKIIα with AIP in a mouse model of retinal toxicity “fully attenuates caspase-3 activation for at least 8 h following NMDA insult and also significantly improves retinal ganglion cell survival” (Abstract).
Thus, as of the filling date, the state of the art teaches changes in CaMKII autophosphorylation was observed after retinal stress and CaMKIIα was primarily interrogated using small molecule or peptide inhibitor. There is no prior art disclosing increasing expression of any CaMK to decrease degeneration of RGCs following excitotoxic stress, and the specification does not provide guidance for overcoming this contradictory teaching or predicting when increasing expression of any CaMK would yield the claimed result. Therefore, a person ordinary skill in the art would need to conduct substantial and unpredictable experimentation to determine whether increasing CaMK expression would increase or decrease degeneration or RGCs as prior art teaches inhibition of CaMKII rather than increased expression, is neuroprotective in RGCs.
In addition, the state of the art teaches degeneration of RGCs involves many different pathways including CaMK and Caspase-3 as taught by both Fan and Goebel. Thus, due to the complexity of ganglion cell health and many ways in which RGCs could degenerate, it is highly unpredictable that merely increasing expression of CaMK would prevent reduction of one or both of retinal ganglion cell somata and retinal ganglion cell axons, as recited in claim 14.
Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to determine which CaMK (including CaMKI, CaMKII, CaMKIV, and isoforms), besides the variants taught by the specification, and expression levels would successfully decrease RGC degeneration.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an unreasonable amount experimentation would be required to make and use the invention as claimed. Therefore, claims 1, 2, 5, 9, 13, and 14 are not considered to be fully enabled by the instant disclosure.
Claims 18, 19, 22, 25, 26, 30, and 31 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.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
Claims are directed to a method of treating vision loss in a subject by increasing activity of a CaMK with a composition comprising the CaMK or a polynucleotide encoding the CaMK.
Breadth of the Claims
With respect to claim breadth, the standard under 35 U.S.C. § 112(a) entails determining what the claims recite and what claims mean as a whole. The claim merely recites treating vision loss in a subject, which under the broadest reasonable interpretation, is interpreted as treating vision loss caused by any disease with merely increasing expression of a CaMK. Further, the breadth of the claims includes a composition that comprises any variants of CaMK and any isoforms of CaMK.
Guidance of the Specification
The teachings of the specification regarding enhancing activity of specific CaMKIIα and CaMKIIβ variants to decrease degeneration of RGCs are discussed above and applied to scope of enablement for claim 1. The specification does not provide any guidance on how to treat vision loss caused by any disease by merely increasing activity of the specific CaMKIIα and CaMKIIβ variants demonstrated in the working examples, let alone any CaMK encompass in the breath of the claims. The specification do not provide any guidance or evidence demonstrating that increased activity of CaMK is broadly applicable to the diverse ways of vision loss, including those that do not involve RGCs degeneration or CaMK-mediated signaling.
State of the Art
At the time of filling, the state of the art demonstrated that vision loss arises from a wide range of ocular diseases involving diverse and distinct pathological mechanisms that are unrelated to CaMK activity, and that gene therapy for neuroprotection of RGCs target numerous different proteins and pathways, not a single kinase such as CaMK. Rhee et al (Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions; Biomolecules, 2021, 11(581)) teaches at least 17 studies utilizing AAV vectors for gene therapy encoding specific genes of interests, which include but are not limited to brain-derived neurotrophic factor, erythropoietin, tropomyosin related receptor kinase-B, Sirtuin 1, and CRISPR/Cas9 (Abstract and Tables 1-4). Rhee also teaches utilizing miRNA to decrease degeneration of RGCs (Table 5). Thus, given this diversity and complexity of pathological context of ocular diseases that contribute to vision loss, it would have been highly unpredictable that merely increasing activity of a CaMK would treat and/or prevent vision loss, and one cannot make and use the claimed invention without substantial and unpredictable experimentation.
Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to screen numerous causes of vision loss (e.g., cataract) and determine which, if any, are affected by increased activity of CaMK.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an unreasonable amount experimentation would be required to make and use the invention as claimed. Therefore, claims 18, 19, 22, 25, 26, 30, and 31 are not considered to be enabled by the instant disclosure.
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 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 36 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Milbrandt et al (US 2016/0367497 A1; Published Date: Dec. 22, 2016) in view of Naso et al (Adeno-Associated Virus (AAV) as a Vector for Gene Therapy; BioDrugs, 2007, 31:317-334).
Regarding claims 36 and 39, Milbrandt teaches an agent comprising a polynucleotide and a vector (abstract), wherein polynucleotide comprises a promoter ([0023]) and encodes a sirtuin polypeptide to increase calcium-calmodulin dependent kinase (referred as CaMKKβ) activity ([0012]). The claim recites wherein the polynucleotide comprises a retinal ganglion cell promoter, which under the broadest reasonable interpretation encompasses any promoter that functions in retinal ganglion cells. Because Milbrandt teaches use of the vector to treat or prevent neuropathies (Abstract), including retinal ganglion degeneration ([0049]), the promoter of Milbrandt necessarily functions in retinal ganglion cells, and therefore, meets the claimed limitation.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Milbrandt's polynucleotide to encode a CaMK, as opposed to a sirtuin polypeptide because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of directly modulating CaMK activity, as opposed to indirectly increasing CaMK activity through an intermediate pathway. One would have had a reasonable expectation of success in doing so because Milbrandt already teaches a polynucleotide that encodes a polypeptide to increase CaMK activity.
However, Milbrandt does not teach the vector and polynucleotide are comprised in a pharmaceutical composition. The specification teaches “a pharmaceutical composition” refers to formulations that “…do not produce an adverse, allergic or other untoward reaction when administered to an animal…” ([0084]). Therefore, a sterile composition meets this claimed limitation because sterility is a routine requirement to avoid microbial contamination and related adverse reactions upon clinical administration.
Naso teaches that products of adeno-associated vectors production contain cellular debris as well as viral particles comprising either full capsids containing the desired transgene or empty capsids lacking the transgene (pg. 324, left column, second paragraph). Naso further teaches that such contaminants must be removed prior to administration, and purification techniques such as affinity resins and anion ion-exchange chromatography are industry-adopted methods that successfully separate full capsids from empty capsids.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Milbrandt's vector to be formulated as a sterile pharmaceutical composition taught by Naso because it would have merely amounted to applying a known technique to a known product ready for improvement to yield predictable results. One would have been motivated to have done so for the advantage of enhancing safety and performance by removing contaminants that could cause an adverse reaction. One would have had a reasonable expectation of success in doing so because Naso teaches established and effective methods for purifying AAV vectors for clinical use.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Milbrandt et al (US 2016/0367497 A1; Published Date: Dec. 22, 2016) in view of Naso et al (Adeno-Associated Virus (AAV) as a Vector for Gene Therapy; BioDrugs, 2007, 31:317-334) as applied to claim 36, and further in view of Dalkara et al (US 2018/0355354 A1; Published Date: Dec. 13, 2018).
Regarding claim 37, the obviousness to modify Milbrandt’s polynucleotide to encode a CaMK in a pharmaceutical composition is discussed above as applied to claim 36.
However, Milbrandt does not teach wherein the vector comprises a retinal ganglion cell promoter, and wherein the promoter comprises a gamma-Synuclein promoter, a Synapsin 1 promoter, or a Neurofilament Heavy promoter, or a Thy-1 cell surface antigen promoter.
Dalkara teaches a gamma-Synuclein promoter that is "suitable for use in combination with AAV vectors, and that can drive high-level gene expression specifically in RGCs" ([0015], [0038], and FIG. 1).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Milbrandt's promoter to a gamma-Synuclein promoter as taught by Dalkara because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of expressing a gene-of-interest in high level, specifically in retinal ganglion cells as taught Dalkara. One would have had a reasonable expectation of success in doing so because both Milbrandt and Dalkara teach polynucleotides comprising promoters that function in retinal ganglion cells.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Milbrandt et al (US 2016/0367497 A1; Published Date: Dec. 22, 2016) in view of Naso et al (Adeno-Associated Virus (AAV) as a Vector for Gene Therapy; BioDrugs, 2007, 31:317-334) as applied to claim 36, and further in view of Fan et al (Retinal ganglion cell death and neuroprotection: Involvement of the CaMKIIα gene; Molecular Brain Research, 2005, 139:306-316).
Regarding claim 41, the obviousness to modify Milbrandt’s polynucleotide to encode a CaMK in a pharmaceutical composition is discussed above as applied to claim 36, and the teachings of Fan are discussed above as applied to claim 41.
However, neither Milbrandt and Fan teach wherein the CaMK is constitutively active.
Fan teaches the nuclear isoform CaMKIIαβ is present in retinal ganglion cells and "there is an early and transient increase in CaMKIIαβ mRNA expression in retinal ganglion cells following glutamate treatment" or retinal ganglion degeneration (pg. 314, right-column, fourth paragraph). Fan therefore, identifies CaMKII as a relevant CaMK involved in retinal ganglion cells.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Milbrandt's polynucleotide to encode a CaMKII to increase CaMK activity because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so by the recognized role and increased expression of CaMKII in retinal ganglion cells. One would have had a reasonable expectation of success in doing so because Milbrandt teaches a polynucleotide encoding a polypeptide to increases CaMK activity.
Claims 43 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Milbrandt et al (US 2016/0367497 A1; Published Date: Dec. 22, 2016) in view of Naso et al (Adeno-Associated Virus (AAV) as a Vector for Gene Therapy; BioDrugs, 2007, 31:317-334) as applied to claim 36, and further in view of Fan et al (Retinal ganglion cell death and neuroprotection: Involvement of the CaMKIIα gene; Molecular Brain Research, 2005, 139:306-316) and Merrill et al (Activity-driven postsynaptic translocation of CaMKII; Trends in Pharmacological Sciences, 2005, 26(12):645-653).
Regarding claims 43 and 44, the obviousness to modify Milbrandt’s polynucleotide to encode a CaMK in a pharmaceutical composition is discussed above as applied to claim 36, and the teachings of Fan are discussed above as applied to claim 41.
However, neither Milbrandt and Fan teach wherein the CaMK is constitutively active.
Merrill teaches Ca2+ influx activates CaMKII through binding of Ca2+/calmodulin to neighboring subunits, which induces autophosphorylation at Thr 286 in CaMKIIα (or Thr 287 in CaMKIIβ) (pg. 645, left column, first paragraph). Merrill further teaches that following autophosphorylation at these residues, CaMKII maintains kinase activity even after Ca2+ concentration falls.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Milbrandt's polynucleotide to encode a CaMKIIα T286D or CaMKIIβ T287D variant, which aspartic acid mimics the negative charge of phosphorylation and the autophosphorylated state, leading to constitutive kinase activity as taught by Merrill. One would have been motivated to have done so because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have also been motivated to have done so for the advantage of increasing and maintaining CaMK activity without relying on upstream Ca2+ signaling or intermediary proteins such as the sirtuin polypeptide of Milbrandt. One would have had a reasonable expectation of success in doing so because Milbrandt teaches a vector capable of expressing a polypeptide to increase CaMK activity and Merrill teaches a structure-function relationship showing that phosphorylation at Thr286 is sufficient to maintain CaMKII kinase activity. Therefore, encoding a CaMKII T286D variant is a predictable alternative to achieve the same outcome, which is to increase CaMK activity.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: Claim 8 is directed to a method of decreasing degeneration of RGCs in a subject, comprising administering to the subject a composition to increase activity of a CaMK, wherein the composition comprises the CaMK selected from one or both of a CaMKIIα T286D variant and a CaMKIIβ T287D variant. Although the closest prior art teaches inhibiting CaMKII using AIP, this neuroprotective strategy for RGCs functions mechanistically different than the instant claimed invention because AIP turns CaMKII off by blocking autophosphorylation of CaMK and prevents its activation toward substrates whereas CaMKIIα T286D and CaMKIIβ T287D variants keep CaMKII on by mimicking the autophosphorylated state which has calcium-independent activity (i.e., autonomous) and allowing activation of substrates.
Claim 8 objected to as being dependent upon a rejected base claim (see discussion above regarding scope of enablement rejection for claim 1), but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowable.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636