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 .
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112(a) – Written Description
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 1-18, 22, and 30 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Claims 1, 10, 15, and 30 recite a method of providing any zinc transporter protein 7 (ZIP7) via a vector or peptide (including any amino acid sequence having at least 90% identity to the sequence of SEQ ID NO: 5) to any cell (including any cell of the retina and any cell of the brain) in any subject to suppress pathological accumulation of any misfolded protein that is associated with any pathology (including any neurodegenerative disease). These claims therefore encompass a wide genus. Dependent claims 3-4, 7, and 9 only individually limit the genera of their respective independent claims, such as to photoreceptor cells of the retina (claim 3), rhodopsin (claim 4 & 9), and retinitis pigmentosa (claim 7). Likewise, claim 22 recites enhancing endoplasmic reticulum (ER)-associated degradation (ERAD) or proteosome-associated degradation in a cell through any method of increasing the expression or activity of any ZIP7 peptide, which encompasses a genus of agents.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genera. MPEP 2163(II)(3)(a)(i)(C).
From the specification, it is clear that applicant is in possession of a method of providing zinc transporter protein 7 (ZIP7) as a vector or peptide with 100% sequence identity to SEQ ID NO: 4-5, and the known sequences outlined on page 14 of the Specification, to photoreceptor cells of the retina of their respective species to suppress pathological accumulation of rhodopsin, including Rh1G69D, associated with retinitis pigmentosa by enhancing ERAD. The specification does not show possession of effectively using one species version of ZIP7 in a different species. For example, the applicant shows no evidence of a method of effectively using the Drosophila ortholog to mammalian ZIP7, Catsup (SEQ ID NO: 4), in any mammal, including in humans, or a method of effectively using human ZIP7 (SEQ ID NOs: 5) in Drosophila. On the other hand, it is clear that the applicant is in possession of a method of using Catsup in Drosophila cells and human ZIP7 in human cells. Likewise, the specification does not disclose any specific sequences within the ZIP7 variants that must be conserved to retain their activity, meaning that the applicant does not show possession of how any sequence with any variation that has 90% identity to SEQ ID NO: 5 can retain its activity and be used in the claimed method. As such, it is clear that applicant is in possession of a method of providing human ZIP7 as a vector or peptide with 100% sequence identity to SEQ ID NO: 5 to photoreceptor cells of the human retina to suppress pathological accumulation of rhodopsin, including Rh1G69D, associated with retinitis pigmentosa by enhancing ERAD. The claims, however, are not limited to those species but also includes a vast array of pathologies, disorders, neurodegenerative diseases, cell types, and proteins. The specification fails to provide a representative number of species within the recited genera. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics of the genera as a whole, or representative number of species within the genera, the specification does not provide adequate written description of the claimed genera.
Claim Rejections - 35 USC § 112(b) – Enablement
Claims 1-18, 22, and 30 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 the species of a method of providing human ZIP7 as a vector or peptide with 100% sequence identity to SEQ ID NO: 5 to photoreceptor cells of the human retina to suppress pathological accumulation of rhodopsin, including Rh1G69D, associated with retinitis pigmentosa by enhancing ERAD, does not reasonably provide enablement for the genera of a method of providing any zinc transporter protein 7 (ZIP7) via a vector or peptide (including any amino acid sequence having at least 90% identity to the sequence of SEQ ID NO: 5) to any cell (including any cell of the retina and any cell of the brain), in any subject to suppress pathological accumulation of any misfolded protein that is associated with any pathology (including any neurodegenerative disease). Likewise, the specification does not reasonably provide enablement for enhancing ERAD or proteosome-associated degradation in a cell through any method of increasing the expression or activity of any ZIP7 peptide (claim 22). 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 factors to be considered in determining whether a disclosure would require undue experimentation include:
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, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed invention is that it covers any method of providing any variation of zinc transporter protein 7 (ZIP7) via a vector or peptide (including any amino acid sequence having at least 90% identity to the sequence of SEQ ID NO: 5) to any cell (including any cell of the retina and any cell of the brain) in any subject to suppress pathological accumulation of any misfolded protein that is associated with any pathology (including any neurodegenerative disease), as well as any method of increasing the expression or activity of any ZIP7 peptide to enhance ERAD or proteosome-associated degradation in any cell. As the breath of the claims encompass a wide scope of compositions, a skilled artisan would not know how to make the composition with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
The specification does not provide direction as to how any and all variants of zinc transporter protein 7 (ZIP7) (including any amino acid sequence having at least 90% identity to the sequence of SEQ ID NO: 5) would be capable of suppressing pathological accumulation of any misfolded protein that is associated with any pathology (including any neurodegenerative disease) in any species. For example, the specification does not provide direction as to how the Drosophila ZIP7 ortholog could be used in humans or how human ZIP7 could be used in Drosophila. Furthermore, the specification does not provide guidance as to what regions of SEQ ID NO: 5 have to be preserved and how any sequence with 90% identity to SEQ ID NO: 5 would retain the required activity to be used in the methods claimed. The art at the time of filing does not provide enabling guidance and the specification as filed does not provide guidance that overcomes this unpredictability within the art.
The existence of working examples:
What is enabled by the working examples is narrow in comparison to the breadth of the claims: the specification discloses Examples 1-4, Figures 1-12, and embodiments within the Sequence Listing, but does not provide working examples for the genera recited above.
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentec, Inc., V. Novo Nordisk, 42 USPQ 2d 100, (CAFC 1997), the court held that: "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" and that "[t]ossing out the mere germ of an idea does not constitute enabling disclosure". The court further stated that "when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all of the disclosure related to the process is within the skill of the art","[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement". The instant specification is not enabling for the full scope of the claimed invention because one cannot follow the guidance presented therein and practice the claimed method without first making a substantial inventive contribution.
Given that the nature of the claimed invention is a method of using any ZIP7 to prevent misfolded proteins associated with any disease, a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials, or in animal models that are predictive of treatment, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to make every embodiment of the claimed invention and to use the method with a reasonable expectation of success. Therefore, the instant claims lack enablement.
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.
Claims 1, 5-6, 10, 15-16, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Groth et al., 2013 in view of Hackett et al., 2003 (US20030220249A1) (see instant PTO-892).
The instant claims are drawn to a method of treating a subject for a disorder associated with protein misfolding, the method comprising administering an expression vector comprising a promoter operably linked to a nucleotide sequence encoding zinc transporter protein 7 (ZIP7) to the subject, wherein the ZIP7 is expressed in vivo in the subject in a therapeutically effective amount sufficient to suppress pathological accumulation of the misfolded protein. The instant claims are drawn to the expression vector being introduced into the cell ex vivo or in vivo. The instant claims are drawn to a method of suppressing accumulation of a misfolded protein in an organ, cell, or tissue of a subject, the method comprising increasing expression or activity of zinc transporter protein 7 (ZIP7) in the organ, cell, or tissue. The instant claims are drawn to the ZIP7 having the sequence as set forth in SEQ ID NO: 5.
Groth teaches that loss or disruption of ZIP7 results in the pathological accumulation of misfolded proteins in the ER and Golgi during tissue formation and organogenesis (abstract). Groth teaches that the Catsup gene in Drosophila encodes the Drosophila ortholog of the mammalian ZIP7 zinc transporter (abstract). Groth teaches a method of using an expression vector in Drosophila, comprising a promotor operably linked to a Catsup coding sequence to suppress the pathological accumulation of misfolded Notch protein (abstract; results; “expression of this wild-type Catsup cDNA under the regulatory control of a daughterless-GAL4 driver line” [Molecular lesions in new Catsup alleles]; “Functional rescue of Notch trafficking defects in Catsup mutant clones expressing transgenic wild-type Catsup-V5. Homozygous Catsup mutant clones were produced in wing discs using the MARCM system to express wild-type Catsup-V5 in the mutant clone cells” [Fig. 3]; & “Localization of transgenically expressed, epitope-tagged Catsup-V5 (red) expressed under regulatory control of patched-GAL4” [Fig. 4]). Groth teaches that dysregulated ZIP7 function plays a role in breast cancer and might also be a contributing factor to other human diseases, including the neurodegenerative disease, Alzheimer′s (Concluding remarks).
While Groth teaches a vector expressing Catsup, Groth does not explicitly teach a vector expressing ZIP7 having the sequence as set forth in SEQ ID NO: 5.
Hacket teaches an amino acid of HKE4 having the sequence set forth in SEQ ID NO: 36 (Db) that has 100% sequence identity to instant SEQ ID NO: 5 (Qy), as shown below. Hackett teaches that HKE4 has a human accession number of AAH00645 (para[0068]), and therefore teaches that HKE4 is another name for ZIP7. Hackett teaches the full-length coding sequence of human HKE4 (Table 1; SEQ ID NOs: 34-35). Hackett teaches that the HKE4 sequence can be administered in an expression vector, comprising a promoter operably linked to a coding sequence, to a cell ex vivo or in vivo to treat a human disease (Table 1; para [0090, 0102-0104, 0120-0125, 0135-0136, & 0156-0159).
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It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosure of Groth and Hacket. Since Groth shows that a vector expressing the Drosophila gene, Catsup, can be used to prevent misfolded Notch in Drosophila and that in mammals the ortholog of Catsup is ZIP7, one with ordinary skill in the art would be motivated to make and use the claimed invention because it would be obvious to use a specific mammalian ZIP7 expression vector, instead of the Drosophila ortholog, to prevent misfolded Notch in a mammal. As such, an ordinary artisan would find it obvious to use the murine version of ZIP7 to prevent misfolded Notch and disordered tissue formation and organogenesis in mice. Since Groth is silent on a specific mammalian ZIP7 expression vector, an ordinary artisan would be motivated to look to the prior art to obtain the appropriate sequence to synthesize and use the vector and would find that Hackett remedies these deficiencies. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-2, 5-6, 10, 12-13, 15-16, 18, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Groth et al., 2013 and Hackett et al., 2003 (US20030220249A1), as applied to claims 1, 5-6, 10, 15-16, and 30 above, in view of Yan et al., 2012 (see instant PTO-892).
Instant claims 1, 5-6, 10, 15-16, and 30 are recited above. The instant claims are drawn to administering the ZIP7 vector directly to a retina cell of the eye.
The teachings of Groth and Hackett how they meet the limitations of claims 1, 5-6, 10, 15-16, and 30 are outlined above in the preceding rejection and are hereby incorporated. Neither prior art reference explicitly teaches that ZIP7 is expressed in the retina or to administer the ZIP7 vector directly to a retina cell.
Yan teaches that ZIP7 is highly expressed in human retina cells, is localized to the ER and Golgi, and that downregulation of ZIP7 in a zebrafish model results in developmental eye defects. (abstract; Discussion, 2nd & 5th para; Results; Figure 1B, 1D, 1E, 1F, and 1G).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Groth, Hackett, and Yan. One with ordinary skill in the art would be motivated to make and use the claimed invention because Yan teaches a specific human tissue, the human retina cells, that highly expresses ZIP7 and is important in eye development. An ordinary artisan would find it obvious that the ZIP7 vector of Groth and Hackett could be administered directly into the retina cells of the eye to suppress protein misfolding in retina cells associated with disordered eye development. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-8, 10-13, 15-18, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Groth et al., 2013, Hackett et al., 2003, and Yan et al., 2012, as applied to claims 1-2, 5-6, 10, 12-13, 15-16, 18, and 30 above, in view of Lin et al., 2010 (see instant PTO-892).
Instant claims 1-2, 5-6, 10, 12-13, 15-16, 18, and 30 are recited above. Instant claims 3-4, 7-8, 11, and 17 are drawn to the retina cell being a photoreceptor cell, the misfolded protein being a misfolded rhodopsin protein, and the disorder associated with protein misfolding being the neurodegenerative disease, retinitis pigmentosa.
The teachings of Groth, Hackett, and Yan and how they meet the limitations of claims 1-2, 5, and 30 are outlined above in the preceding rejection and are hereby incorporated. None prior art references explicitly teach the retina cell being a photoreceptor cell, the misfolded protein being a misfolded rhodopsin protein, and the disorder associated with protein misfolding being the neurodegenerative disease, retinitis pigmentosa.
Lin teaches that the accumulation of misfolded rhodopsin in retinal photoreceptor cells is associated with retinitis pigmentosa and retinal degeneration (abstract; 14.1 Endoplasmic Reticulum Stress and Retinal Degeneration; & 14.2 Misfolded Proteins in Photoreceptors). Lin teaches that “preventing rhodopsin misfolding may be a new strategy to prevent retinal degeneration. This approach may also be efficacious in other retinal diseases arising from protein misfolding” (14.4 Pharmacologic Targeting of Protein Misfolding to Prevent Retinal Degeneration).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Groth, Yan, Hackett, and Lin. One with ordinary skill in the art would be motivated to make and use the claimed invention because Lin directly implicates a specific human disease associated with specific protein misfolding in photoreceptor cells. An ordinary artisan would find it obvious that the vector of Groth and Hackett combined with Yan’s teaching that ZIP7 is highly expressed in the retina could be used in the context of human photoreceptor cells to suppress misfolded rhodopsin associated with retinitis pigmentosa. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Ohashi et al., 2016 (see instant PTO-892).
Instant claim 22 is drawn to a method of enhancing endoplasmic reticulum (ER)-associated degradation (ERAD) or proteosome-associated degradation in a cell, the method comprising increasing expression or activity of zinc transporter protein 7 (ZIP7) in the cell.
Ohashi teaches “Misfolded proteins are transported across the ER membrane for cytosolic proteasome degradation in a process known as ER-associated degradation (ERAD). Key ERAD components include E3 ubiquitin ligases that are embedded in the ER membrane. Most ERAD E3 ligases possess a zinc-coordinating RING domain to facilitate E2-dependent ubiquitylation. The formation of a rigid, globular platform for protein-protein interactions in RING fingers requires zinc, implying that fine-tuning zinc concentration by ZIP7 seems to be essential for normal ER function” (Introduction).
Oshashi does not explicitly teach a method where increasing ZIP7 expression enhances ERAD.
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Ohashi. One with ordinary skill in the art would be motivated to make and use the claimed invention because Ohashi teaches the specific mechanism through which ZIP7 suppresses the accumulation of misfolded proteins. It would be obvious in view of Oshashi that increasing from abnormal zero expression to normal expression by increasing expression of ZIP7 to enhance ERAD. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-18, 22, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Groth et al., 2013, Hackett et al., 2003 (US20030220249A1), Yan et al., 2012, Lin et al., 2010, and Ohashi et al., 2016 as applied to claims 1-8, 10-13, 15-18, 22, and 30 above, in view of Xu et al., 2020 (see instant PTO-892).
Instant claims 1-8, 10-13, 15-18, 22, and 30 are recited above. Instant claims 9 and 14 are drawn to the misfolded protein being Rh1G69D rhodopsin, Vap33, or amyloid p42.
The teachings of Groth, Yan, Li, Hackett, and Ohashi and how they meet the limitations of claims 1-8, 10-13, 15-18, 22, and 30 are outlined above in the preceding rejection and are hereby incorporated. None of these prior art references explicitly teaches the misfolded protein being Rh1G69D rhodopsin, Vap33, or amyloid p42.
Xu teaches that Rh1G69D rhodopsin accumulates in the ER, causes ER stress, and triggers photoreceptor cell degeneration and that the E3 ubiquitin ligases SORDD1 and SORDD2 effectively suppressed Rh1G69D-induced photoreceptor dysfunction and retinal degeneration (abstract). Xu teaches “that SORDD1 and SORDD2 belong to conserved RING-finger motifs and transmembrane regions E3 ligase family” (Results, SORDD1 and SORDD2 are new suppressors of Rh1G69D).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Groth, Yan, Li, Hacket, Ohashi, and Xu. One with ordinary skill in the art would be motivated to make and use the claimed invention because Ohashi teaches a specific mutated version of rhodopsin that causes photoreceptor dysfunction. Since Lin teaches that misfolded rhodopsin is associated with retinitis pigmentosa, an ordinary artisan would find it obvious that a specific rhodopsin mutation that accumulates and causes photoreceptor cell degeneration could be targeted with the method of administering ZIP7. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
No claims are allowed.
Advisory Information
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/JOSEPH D. CESARE/
Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
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