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 .
Election/Restrictions
Applicant’s election of Group I, claims 1, 5-15 and 17-26 in the reply filed on 02/27/2026 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)). In addition, Applicant elected SEQ ID NO: 70, though the search was expanded to include SEQ ID NOs: 71-74.
Claims 56, 57 and 59 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/27/2026.
Claims 1, 5-15 and 17-26 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) is acknowledged. Based on the information given by Applicant and an inspection of the prior applications, the examiner has concluded that the subject matter defined in the instant claims is supported by the disclosure in provisional application serial no. 63/480,279, but not provisional application serial nos. 63359168 or 63316298 because the claimed invention is not disclosed in either the ‘168 or ‘298 provisional application. The priority date of claims 1, 5-15 and 17-26 is deemed to be 01/17/2023.
Drawings
Applicant’s petition filed 03/02/2023 under 37 CFR 1.84(a)(2) to accept color drawings was granted on 09/22/2023.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: TARGETING PEPTIDES CAPABLE OF BINDING TO CARBONIC ANHYDRASE IV FOR CROSSING BLOOD BRAIN BARRIER.
Claim Objections
Claim 1 is objected to because of the following informalities. Claim 1 recites “carbonic acid anhydrase IV”, but presumably “carbonic anhydrase IV” was intended.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 5 is 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 5 depends from claim 1 and recites that the permeability of the blood brain barrier is increased by at least 25%, 50%, 75%, 100%, or more as compared to the absence of the target peptide or the reduction of carbonic anhydrase IV activity. First, it is not clear how the blood brain barrier could be increased by more than 100%. Second, “or more” following the phrase is reasonably interpreted as modifying each of the percentages, thus, 25% or more, 50% or more, etc. The phrase “or more” is indefinite because it cannot be determined what value is encompassed by “or more”. Is 25% or more greater or less than 50% or 75%? The claims must particularly point out and distinctly define the metes and bounds of the subject matter that will be protected by the patent grant (see MPEP 2171).
Claim Rejections - 35 USC § 112(a)
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.
Enablement
Claims 1, 5-15 and 17-26 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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988). 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.
The claims are broad with regard to the targeting peptide, which is required to increase permeability of the blood brain barrier by 25-100% (claims 1, 5), as well as:
bind a zinc binding site and/or hydrophobic substrate binding pocket of the carbonic acid anhydrase IV or a derivative thereof, wherein said derivative may have at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 179 or SEQ ID NO: 180 (claims 1, 6, 15);
capable of interacting with (1) one or more positions functionally equivalent to S20, G21, W22, L36, W41, P42, E90, V111, Q112, H114, H139, V141, K143, F156, L217, T218, T219, P220, N221, D223, or W228 in the carbonic anhydrase IV having an amino acid sequence of SEQ ID NO: 179; or (2) one or more positions functionally equivalent to S21, H22, W23, L37, W42, G43, M92, K113, Q114, H116, H141, V143, E145, Q158, L224, T225, T226, P227, T228, D231, or W236 in the carbonic anhydrase IV having an amino acid sequence of SEQ ID NO: 180 (claims 6, 17);
may have 80% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 70-174 (claims 6, 18, 19); and
wherein the targeting peptide is inserted between two adjacent amino acids in AA587-594 (or AA588-589) of SEQ ID NO: 178 of the AAV9 vector or functional equivalents thereof in an amino acid sequence at least 80% identical to SEQ ID NO: 178 (claims 8, 9, 20, 21).
The claimed methods also encompass methods of delivering a payload to a nervous system comprising providing a targeting peptide capable of binding to a carbonic anhydrase IV or derivate thereof, wherein the targeting peptide is part of a delivery system (claims 6-15 and 17-26). Claim 14 encompasses delivery of a nucleic acid sequence to the nervous system comprising:
a trophic factor, a growth factor, or other soluble factors that might be released from the transduced cells and affect the survival or function of that cell and/or surrounding cells;
a cDNA that restores protein function to humans or animals harboring a genetic mutation(s) in that gene;
a cDNA that encodes a protein that can be used to control or alter the activity or state of a cell;
a cDNA that encodes a protein or a nucleic acid used for assessing the state of a cell;
a cDNA and/or associated guide RNA for performing genomic engineering;
a sequence for genome editing via homologous recombination;
a DNA sequence encoding a therapeutic RNA;
an shRNA or an artificial miRNA delivery system; or
a DNA sequence that influences the splicing of an endogenous gene.
The claims encompass a large patient population, including those suffering from the conditions recited in claims 25 and 26. In summary, the claims are broad with respect to the targeting peptide and methods of treatment.
The specification discloses murine Ly6c1 and carbonic anhydrase IV as targets for crossing the blood brain barrier (see Example 2, pages 78-83) and peptides and engineered AAVs for crossing the blood brain barrier (see Example 3, pages 83-89). The targeting peptides are disclosed as SEQ ID NOs: 11, 12 and 70-174 (see paragraph [0098]). The specification describes Automated Pairwise Peptide Receptor Analysis for Screening Engineered AAVs (APPRAISE), which predicts receptor binding capacity in silico at paragraphs [0026] and [0235]-[0239] and multiplexed-Cre recombination-based AAV targeted evolution (M-CREATE), which is an in vivo screening platform using a humanized mouse model at paragraphs [0025], [0145], [240] and [0255]. In describing M-CREATE, the specification discloses that a “proof-of-concept” using “the murine receptor Ly6c1 (vs. the human Car4) was chosen due to the prompt availability of (1) strains with clear BBB differences, e.g. Ly6a, and (2) diverse Cre-transgenic animals for M-CREATE selections that were not available for Car4 in other species” (paragraph [0255]). See also paragraph [0256] of the instant specification:
Using M-CREATE, scanning 3-mer substitution capsid libraries were constructed in the chemically-diverse Ly6c1-interacting variants PHP.C1, PHP.C2, PHP.C3, and PHP.C4. These libraries were pooled for two rounds of selection in Syn-Cre mice (FIG. 5A). In the second round of selection, Olig2-Cre, Tek-Cre, and GF AP-Cre mice, as well as wild-type C57BL/6J and BALB/cJ mice were also included so that potential differences in enhancement between these strains or cell types could be detected during selection among the variants (FIG. 5B). Interestingly, while PHP.C2 variants dominated both rounds of selection in the C57BL/6J background (Cre-dependent or not), PHP.C1 variants dominated the round 2 Cre-independent selection in BALB/cJ (FIG. 12). Following selection, top-performing variants were individually produced and characterized. AAV-PHP.eC (variant 19), evolved from PHP.C1, retained Ly6c1 interaction in cell culture (FIG. 5C) and outperformed PHP.C2 in multiple mouse strains with membrane-disrupted Ly6a (FIG. 5D). PHP.eC, thus, provided a potent tool for transgene delivery in mouse strains without membrane-localized Ly6a.
Thus, it does not appear that the carbonic acid anhydrase IV targeting peptides were tested in an M-CREATE platform.
The specification discloses Table 2, which lists SEQ ID NOs: 70-177 by APPRAISE-AAV score, with B_POI representing the energetic binding score (see pages 38-40), where higher values indicate better binding affinity. As noted above, these in silico pre-screened peptides were not tested in vivo. See paragraph [0263] of the instant specification:
In mouse Car4, 9P31 peptide invaded the catalytic pocket of the enzyme (FIG. 7A). The 9P31 tyrosine residue shared with 9P36 approaches the enzyme active site and 9P31's divergent tryptophan finds purchase in an ancillary pocket (FIG. 7B). This predicted binding pose was competitive with the binding site of brinzolamide (PDB ID 3NZC), a broad carbonic anhydrase inhibitor that is prescribed for glaucoma. In the cell culture infectivity assay, brinzolamide showed a dose-dependent inhibition of 9P31 and 9P36 potency, while PHP.eB was unaffected (FIG. 7B). The smaller brinzolamide bound deep in the catalytic core of Car4 where side chains were largely conserved between species (FIG. 7C). However, 9P31 peptide extended to the surface of the enzyme where there was considerable sequence divergence. Similarly, while brinzolamide bound to both mouse and human Car4, 9P31 and 9P36 were specific to mouse Car4 (FIG. 7D). Chimeric receptors that swapped a highly divergent loop of the 9P31 binding site showed that this region was necessary but not sufficient to control 9P31 and 9P36 potency. A second potential Car4 binding site was also suggested by lower ranked poses with 9P31 and 9P36, but mutagenesis experiments showed inconsistent effects (FIG. 14B). Future rational engineering of new AAVs against species-appropriate CA4 [carbonic anhydrase 4], aided by the APPRAISE-AA V method, is a promising new avenue for the generation of non-invasive vectors with enhanced CNS potency. Targeting CA4 can also find applications across diverse proteins and chemical modalities. In vivo experiments can be carried out to further validate the engineering of a human CA-binding AAV with optimal BBB crossing properties.
Thus, the specification indicates that future experimentation must be undertaken to verify human carbonic anhydrase IV binding to enable crossing of the blood brain barrier in vivo. The post-filing date art of Lin et al. (Cell Reports, 2025; 44: 116419) teaches a humanized mouse model expressing carbonic anhydrase IV for the “rapid assessment of translational AAVs” (see “Highlights”), and emphasizes the importance of in vivo screening (see p. 10, left column, last paragraph):
Interestingly, the most effective BBB-crossing human CA-IV-dependent variants that we identified (AAV-hCA4-IV68 and AAV-hCA4-IV77) arose from a hybrid in vitro/in vivo selection pipeline, rather than a fully in vitro approach. While several top-ranked variants from fully in vitro selection (Alpha 48, 49, and 62) showed strong human CA-IV-dependent boosts in cell transduction, they performed poorly in vivo. Conversely, the top two in vivo capsids were relatively lower ranked in vitro round 1 performers within the top 0.01% (10,000 variants) chosen for inclusion in round 2 selection. This highlights the value of in vivo selections using “humanized” mice and suggests a limitation for AAV engineering based solely on in vitro selection wherein stringent thresholds for in vitro performance may risk missing potent in vivo vectors.
Given that the claims encompass binding to particular portions of carbonic acid anhydrase IV to facilitate increasing permeability of the blood brain barrier and treatment of a large variety of conditions, the evidence of record is not commensurate in scope with the breadth of the recited targeting peptides.
The specification encompasses targeting peptides that differ from SEQ ID NOs: 70-174 by up to 20%. The number of mutations generally possible in any given peptide that can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the peptide’s structure/function relationship, e.g., such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. The specification discloses APPRAISE and M-CREATE, which may accelerate the development of engineered adeno-associated virus (AAV) vectors with specific, enhanced tropisms. Nevertheless, the art provides evidence that mutations can be destabilizing and their effects unpredictable. For example, the specification discloses that SEQ ID NO: 70 has an energetic binding score (B_POI) of 113.5, while SEQ ID NO: 109 has a B_POI of only 49.5, yet they share a local similarity of 87.5%. Ding et al. (Molecular Therapy, 2024; Vol. 32: 1687-1700) disclose (see p. 1696, left column penultimate paragraph through right column, 1st paragraph):
As a competition-based ranking method, APPRAISE faces several intrinsic limitations. One such limitation is that APPRAISE only outputs the relative, not the absolute, probability of binding. Therefore, unless there are positive controls with known binding to compare against, a variant’s position at the top of the ranking does not indicate that the variant has an experimentally detectable binding affinity. Another limitation lies in APPRAISE’s assumption that the binding of competing proteins is mutually exclusive. Counterexamples arise if the competing proteins exhibit cooperative binding or attach to epitopes situated at a considerable distance. Furthermore, certain candidate proteins may exhibit a tendency to interact with one another rather than with the designated target receptor. Additionally, the geometrical scores utilized in APPRAISE 1.1+ were computed assuming the target receptor has a predominantly convex structure. Thus, these scores are most effective when applied to single protein domains with convex shapes.
Other limitations of APPRAISE may arise from the protein structure prediction engine that it relies on. For example, ESMFold-APPRAISE fails when the language-model-based structure prediction tool cannot properly fold the protein in a complex (Figure S5B). At the same time, AF-Multimer-APPRAISE results can be biased by the specific selection of multiple sequence alignments due to the dependence on coevolutionary information by AF-Multimer…Additionally, the APPRAISE method is ineffective in ranking weak binders in a pool (e.g., Figure 3G), perhaps because the predicted structures do not offer many opportunities for meaningful interaction, resulting in near-zero competition scores.
The specification also discloses the AlphaFold in silico model for screening candidate peptides (see paragraphs [0110]; [0235]; [0263]). Pak et al., PLoS ONE 18(3): e0282689. https://doi.org/10.1371/journal.pone.0282689) teach that even in the case of single mutations, AlphaFold intelligence programs do not accurately “predict the impact of mutation on protein stability” or function (see p. 2, 2nd paragraph and p. 7, 1st full paragraph). In the instant case, the claims and specification encompass up to a 20% divergence from SEQ ID NOs: 70-174 and claims 109-177 have a B_POI less than 50. Although the specification outlines art-recognized procedures for producing and screening for active muteins, this is merely an invitation to the artisan to use the current invention as a starting point for further experimentation to find targeting peptides capable of crossing the blood brain barrier and to treat the encompassed diseases, including via gene therapy.
The claims are broad with respect to the patient population and disease/ conditions treated. Further, treatment of neurological diseases is complicated. Regarding the treatment of neurodegenerative diseases, a review by Van Bulck et al. (Int. J. Mol. Sci. 2019, 20, 719; doi:10.3390/ijms20030719; 36 pages total) notes that “[n]eurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells,” (see p. 1, 1st sentence). Van Bulck et al. note that there is still no effective treatment currently available to reverse or prevent the course of neurodegenerative diseases (see p. 2, 1st full paragraph). In addition, the instant specification defines treatment as encompassing prevention (see paragraph [0191]) and Van Bulck et al. teach that “no current therapies can prevent, slow, or halt progression” of neurodegenerative diseases (see abstract). By way of example, the art recognizes that Alzheimer's disease has many features, including short-term memory loss, behavioral abnormalities, as well as a multitude of anatomical abnormalities such as the presence of both amyloid plaques and neurofibrillary tangles, but there is disagreement regarding the pathophysiology of the disease. See Herz (Neuron, 2007; 53: 477-479), which teaches that our mechanistic understanding of AD remains in the nascent stage (p. 478, right column, last paragraph).
The claims also encompass gene therapy. Relevant literature indicates that gene therapy with antisense, siRNA and shRNA is complex. For instance, the review by Hu et al. (Signal Transduction and Targeted Therapy (2020) 5:101) provides background on the current state of the art of siRNA therapy. Hu et al. outline the challenges to siRNA therapy (p. 2, left column, 2nd paragraph):
Although siRNA holds promising prospects in drug development, several intracellular and extracellular barriers limit its extensive clinical application. Naked and unmodified siRNA possesses some disadvantages, such as (1) unsatisfactory stability and poor pharmacokinetic behavior and (2) the possible induction of off-target effects. The phosphodiester bond of siRNA is vulnerable to RNases and phosphatases. Once it is systematically administered into circulation, endonucleases or exonucleases throughout the body will quickly degrade siRNA into fragments, thus preventing the accumulation of intact therapeutic siRNA in the intended tissue. In theory, siRNA only functions when its antisense strand is completely base-paired to the target mRNA. However, a few mismatches are tolerated by the RNA-induced silencing complex (RISC), which may lead to undesired silencing of those genes with a few nucleotide mismatches.
Hu et al. review the techniques undertaken to deal with the challenges of siRNA therapy, which serve to underscore the complexity of the field. For instance, base modification is a promising technique, but one that is “basically at the stage of research and development” (see discussion under “Base modification in the paragraphs bridging the left and right columns of p. 6). Regarding siRNA delivery, Hu et al. teach:
Only 1–2% of internalized LNP [lipid nanoparticle]-loaded siRNAs were released into the cytoplasm, and this only occurred within a limited time frame after internalization. Hence, further understanding the escape mechanism and how to enhance the escape efficiency is of great importance for siRNA drug development (p. 11, left column, 1st paragraph—Citations omitted by examiner).
In spite of progress made in the field of siRNA drug development and delivery, Hu et al. underscore the complexity of a field that is still in its developmental stage.
The specification discloses in silico and in vitro methods for screening AAV variants. Nevertheless, relevant literature teaches despite having made strides over the past 40 years, gene therapy remains unpredictable (see the abstract of Antoine Gardin and Giuseppe Ronzitti, Archives de Pédiatrie 30 (2023) 8S46–8S52—hereafter “Gardin”). For instance, effective treatment of chronic conditions would require AAVs to persist in cells, which is also complex and unpredictable (see p. 8S49, right column, 2nd paragraph):
[T]he presence of chronic tissue damages due to the underlying disease could induce remaining cell proliferation and therefore progressive loss of correction unless AAV vectors achieve a complete correction of the phenotype. This has been suggested in animal models of chronic liver disease, but also in diseases involving the central nervous system. For instance, in animal models of Krabbe disease, a lysosomal storage disease affecting neurons and oligodendrocytes due to the accumulation of a toxic metabolite (psychosine), the use of AAV vectors allowed the initial correction of the phenotype followed by a slow resurgence of the disease: the accumulation of psychosine led to the focal loss of oligodendrocytes, with compensatory proliferation and vector dilution in the surrounding oligodendrocytes, leading to the self-propagation of the demyelination and ultimately to a loss of correction. (Citations omitted by examiner).
In summary, while Gardin teaches that methods of using adeno-associated viral (AAV) vectors for transducing DNA have improved, using RNA- or DNA-based therapies was was still unpredictable in the art at the time of filing of the instant application, and the limited teachings of the instant application, which do not actually test the ability of the peptides of interest to cross the blood brain barrier, do not overcome these shortcomings.
Due to the large quantity of experimentation necessary to treat the encompassed conditions by increasing permeability of the blood brain barrier by administering a targeting peptide capable of binding to a carbonic anhydrase IV or a derivative thereof, the lack of direction/guidance presented in the specification regarding the ability of these targeting peptides to aid in the treatment of the encompassed neurodegenerative conditions, many of which are incurable, the absence of working examples directed to the same, the complex nature of the invention, the unpredictability of the effects of mutation on protein structure and function, and the breadth of the claims which fail to recite limitations on the targeting peptides, the carbonic anhydrase IV and the diseases/ conditions treated, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Written Description
Claims 1, 5-15 and 17-26 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. This is a written description rejection.
The claims are drawn to methods of providing/administering a targeting peptide, which is required to increase permeability of the blood brain barrier by 25-100% or delivering a payload to a nervous system comprising providing a targeting peptide capable of binding to a carbonic anhydrase IV or derivate thereof, wherein the targeting peptide is part of a delivery system (claims 1, 5-15 and 17-26). The claims recite that the targeting peptide be able to bind a zinc binding site and/or hydrophobic substrate binding pocket of the carbonic acid anhydrase IV or a derivative thereof, wherein said derivative may have at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 179 or SEQ ID NO: 180 (claims 1, 6, 15). Further, the targeting peptide:
must be capable of interacting with (1) one or more positions functionally equivalent to S20, G21, W22, L36, W41, P42, E90, V111, Q112, H114, H139, V141, K143, F156, L217, T218, T219, P220, N221, D223, or W228 in the carbonic anhydrase IV having an amino acid sequence of SEQ ID NO: 179; or (2) one or more positions functionally equivalent to S21, H22, W23, L37, W42, G43, M92, K113, Q114, H116, H141, V143, E145, Q158, L224, T225, T226, P227, T228, D231, or W236 in the carbonic anhydrase IV having an amino acid sequence of SEQ ID NO: 180 (claims 6, 17);
may have 80% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 70-174 (claims 6, 18, 19); and
is inserted between two adjacent amino acids in AA587-594 (or AA588-589) of SEQ ID NO: 178 of the AAV9 vector or functional equivalents thereof in an amino acid sequence at least 80% identical to SEQ ID NO: 178 (claims 8, 9, 20, 21).
In summary, the claims encompass a large genus of targeting peptides with a high degree of variability and the ability to treat disease.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The MPEP 2163(A) states “‘[a]n invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.’” For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession (see MPEP 2163(II)(A)(3)(a)(i)).
In deciding whether the application complies with the written description requirement of 35 USC 112(a) or 35 USC 112 (pre-AIA ), first paragraph, it is necessary to understand what Applicant is claiming (see above) and what Applicant has possession of. From the specification, it is clear that Applicant has possession of SEQ ID NOs: 70-174, which are shown to have energetic binding scores (B_POI) of between 113.5 (SEQ ID NO: 70) and 2.9 (SEQ ID NO: 174). The specification describes Automated Pairwise Peptide Receptor Analysis for Screening Engineered AAVs (APPRAISE), which predicts receptor binding capacity in silico at paragraphs [0026] and [0235]-[0239] and multiplexed-Cre recombination-based AAV targeted evolution (M-CREATE), which is an in vivo screening platform using a humanized mouse model at paragraphs [0025], [0145], [240] and [0255]. In describing M-CREATE, the specification discloses that a “proof-of-concept” using “the murine receptor Ly6c1 (vs. the human Car4) was chosen due to the prompt availability of (1) strains with clear BBB differences, e.g. Ly6a, and (2) diverse Cre-transgenic animals for M-CREATE selections that were not available for Car4 in other species” (paragraph [0255]). See also paragraph [0256] of the instant specification, which disclose that SEQ ID NOs: 70-174 were not subjected to the M-CREATE assay. In summary, while the specification discloses how to test potential targeting peptides for the ability to carry out the required functions, it does not disclose how the targeting peptide can differ from SEQ ID NOs: 70-174 by up to 20% while retaining the required functions. Furthermore, targeting peptides may bind to carbonic anhydrase that shares only 80% sequence identity to wild-type (e.g., claims 20, 21). Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). With the exception of SEQ ID NOs: 70-174, the skilled artisan cannot envision the detailed chemical structure of the encompassed peptides, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, only peptides comprising the amino acid sequences set forth in SEQ ID NOs: 70-174, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Some prior art documents disclose sequences sharing ≥ 80% sequence identity to SEQ ID NOs: 70-74. For instance, some representative alignments are presented herein:
Match between instant SEQ ID NO: 74 and SEQ ID NO: 723608 of US Patent No. 10,706,955:
RESULT 2
US-13-052-733-723608
(NOTE: this sequence has 1 duplicate in the database searched)
Sequence 723608, US/13052733
Patent No. 10706955
GENERAL INFORMATION
APPLICANT: ioGenetics, LLC
APPLICANT: Bremel, Robert D.
APPLICANT: Homan, Jane
TITLE OF INVENTION: Bioinformatic Processes for Determination of Peptide Binding
FILE REFERENCE: IOGEN-31239/US-3/ORD
CURRENT APPLICATION NUMBER: US/13/052,733
CURRENT FILING DATE: 2011-03-21
PRIOR APPLICATION NUMBER: US 61/394,130
PRIOR FILING DATE: 2010-10-18
PRIOR APPLICATION NUMBER: US 61/316,523
PRIOR FILING DATE: 2010-03-23
NUMBER OF SEQ ID NOS: 3407294
SEQ ID NO 723608
LENGTH: 18
TYPE: PRT
ORGANISM: Mycobacterium
Query Match 52.6%; Score 40; Length 18;
Best Local Similarity 80.0%;
Matches 8; Conservative 1; Mismatches 1; Indels 0; Gaps 0;
Qy 3 PPLLGGLAQA 12
||||| |||:
Db 5 PPLLGELAQS 14
Match between instant SEQ ID NO: 71 and the peptide disclosed in Figure 1 of Jo et al. (US20100197598).
RESULT 2
US-12-524-935-624
Sequence 624, US/12524935
Patent No. 8629097
GENERAL INFORMATION
APPLICANT: JO, DAE WOONG
APPLICANT: KO, JAE SUN
APPLICANT: KIM, JIN SOOK
APPLICANT: PARK, KYUNG MI
APPLICANT: SONG, JIN KYUNG
APPLICANT: LIM, JUNG HEE
APPLICANT: DO, THI THUY NGA
APPLICANT: DO, THI LAN PHUONG
APPLICANT: DUONG, MINH TAM
TITLE OF INVENTION: NOVEL MACROMOLECULE TRANSDUCTION DOMAINS AND METHODS FOR
TITLE OF INVENTION: IDENTIFICATION AND USES THEREOF
FILE REFERENCE: 346234US0PCT
CURRENT APPLICATION NUMBER: US/12/524,935
CURRENT FILING DATE: 2010-04-15
PRIOR APPLICATION NUMBER: PCT/KR08/000525
PRIOR FILING DATE: 2008-01-29
PRIOR APPLICATION NUMBER: 60/887,060
PRIOR FILING DATE: 2007-01-29
NUMBER OF SEQ ID NOS: 996
SEQ ID NO 624
LENGTH: 22
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide
Query Match 53.4%; Score 39; Length 22;
Best Local Similarity 81.8%;
Matches 9; Conservative 0; Mismatches 2; Indels 0; Gaps 0;
Qy 5 PLLLLLQAQTG 15
|||||| | ||
Db 9 PLLLLLVATTG 19
Nevertheless, the prior art documents do not teach or suggest using the instantly claimed peptides to increase the permeability of the blood brain barrier or deliver a payload to the central nervous system.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
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, Jeffrey Stucker can be reached at 5712720911. 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.
/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
Prosecution Insights