Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed September 5, 2025.
Amendments
Applicant's response and amendments, filed September 5, 2025, is acknowledged. Applicant has cancelled Claims 1-2, 4-14, 16, 18-19, 21, 23-28, 30-34, 36, 38-39, 41-45, 47-48, and 50-59, amended Claims 3, 15, 17, 20, 22, 29, 35, 37, 40, 46, and 49, and added new claims, Claims 60-66.
Claims 3, 15, 17, 20, 22, 29, 35, 37, 40, 46, 49, and 60-66 are pending.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on September 5, 2025 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
Allowable Subject Matter
1. Claims 20 and 40 recite allowable subject matter.
The following is a statement of reasons for the indication of allowable subject matter:
Claims 20 and 40 recite the nucleotide sequence of SEQ ID NO:10, which appears to be a codon-optimized nucleotide sequence encoding human VPS35 composed of the amino acid sequence of SEQ ID NO:1.
Lucking et al (U.S. 2014/0371098) is considered relevant prior art for having disclosed a cDNA encoding human VPS35 (SEQ ID NO:892; Table A) which is 97% identical to instant SEQ ID NO:10 (upper line), encodes an amino acid sequence that is 100% identical to instant SEQ ID NO:1, and comprises 42 disparate mismatches, examples of which are shown below:
Qy 61 CAGGCTGTGAAGGTCCAGTCATTCCAAATGAAGAGATGCCTGGACAAAAACAAGCTCATG
|||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||
Db 61 CAGGCTGTGAAGGTCCAGTCATTCCAAATGAAGAGATGCCTGGACAAAAACAAGCTTATG
Qy 301 GCTGGAAACATTATCCCAAGGCTTTACCTTCTGATCACAGTTGGAGTTGTATATGTCAAG
|||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||
Db 301 GCTGGAAACATTATCCCAAGGCTTTACCTTTTGATCACAGTTGGAGTTGTATATGTCAAG
Qy 361 TCATTTCCTCAGTCCAGGAAGGATATTCTGAAAGATTTGGTAGAAATGTGCCGTGGTGTG
||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||
Db 361 TCATTTCCTCAGTCCAGGAAGGATATTTTGAAAGATTTGGTAGAAATGTGCCGTGGTGTG
Qy 541 GATTTCGTACTGCTCAACTTTGCAGAAATGAACAAGCTCTGGGTGCGAATGCAGCATCAG
||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 GATTTTGTACTGCTCAACTTTGCAGAAATGAACAAGCTCTGGGTGCGAATGCAGCATCAG
Qy 781 TATCTCATGGAGTGTATTATTCAGGTATTCCCTGATGAATTTCACCTCCAGACTTTGAAT
|||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||
Db 781 TATCTCATGGAGTGTATTATTCAGGTTTTCCCTGATGAATTTCACCTCCAGACTTTGAAT
Qy 841 CCTTTCCTTCGGGCCTGTGCTGAGTTACACCAGAATGTAAATGTGAAGAACATAATCATT
||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 CCTTTTCTTCGGGCCTGTGCTGAGTTACACCAGAATGTAAATGTGAAGAACATAATCATT
Qy 1201 CTATTGAAAATACCAGTTGACACTTACAACAATATATTAACAGTCTTGAAATTAAAACAT
|| |||||||||||||||||||||||||||||||| ||||||||||||||||||||||||
Db 1201 CTTTTGAAAATACCAGTTGACACTTACAACAATATTTTAACAGTCTTGAAATTAAAACAT
Qy 1261 TTCCACCCACTCTTTGAGTACTTTGACTACGAGTCCAGAAAGAGCATGAGTTGTTATGTG
|| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 TTTCACCCACTCTTTGAGTACTTTGACTACGAGTCCAGAAAGAGCATGAGTTGTTATGTG
Qy 1321 CTTAGTAATGTTCTGGATTATAACACAGAAATTGTATCTCAAGACCAGGTGGATTCCATA
||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||
Db 1321 CTTAGTAATGTTCTGGATTATAACACAGAAATTGTCTCTCAAGACCAGGTGGATTCCATA
Qy 1501 GAGGACCCTGACCAGCAGTACTTGATATTGAACACAGCACGAAAACATTTCGGAGCTGGT
|||||||||||||||||||||||||| ||||||||||||||||||||||| |||||||||
Db 1501 GAGGACCCTGACCAGCAGTACTTGATTTTGAACACAGCACGAAAACATTTTGGAGCTGGT
Qy 1801 ACAGTCGCATATGAATTCATGTCCCAGGCATTCTCTCTGTATGAAGATGAAATCAGCGAT
|||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||
Db 1801 ACAGTCGCATATGAATTCATGTCCCAGGCATTTTCTCTGTATGAAGATGAAATCAGCGAT
Qy 2341 CGGGAATCACCAGAATCCGAGGGGCCAATTTATGAAGGACTCATCCTTTAA 2391
|||||||||||||||||||||||||||||||||||||| ||||||||||||
Db 2341 CGGGAATCACCAGAATCCGAGGGGCCAATTTATGAAGGTCTCATCCTTTAA 2391
The prior art does not appear to teach or fairly suggest the codon-optimized nucleotide sequence of SEQ ID NO:10.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
2. The prior rejections of Claims 9, 11, and 13 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, are withdrawn in light of Applicant’s cancellation of the claims.
3. The prior rejection of Claims 3, 7-9, 11, 13-14, and 59 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to Claim 3 cancelling recitation of “a therapeutically effective amount”.
4. Claims 3, 15, 17, 20, 22, 29, 35, 37, 40, 46, 49, and 60-66 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.
Claims 3 and 35 have been amended to recite the step of introducing into a neuronal cell at least one vector comprising:
i) a transgene encoding retromer core protein VPS35, and
ii) a transgene encoding retromer core protein VPS26a (Claim 3) or VPS26b (Claim 35) [structure],
wherein, when the one or more vectors are introduced into the neuronal cell:
(a) the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) are increased in the neuronal cell relative to the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell, thereby increasing retromer function [function 1]; and/or
(b) the levels of Sorl1 are increased in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell [function 2], thereby increasing retromer function.
The claims also denote that there is an amount (syn. dosage) of the nucleic acid vectors and/or one or more presently unrecited transcriptional regulatory elements operably linked to the first and second transgenes, respectively, that upon introduction into the neuronal cell, is not, in fact, effective or able to achieve the first and/or second recited functional properties, thereby increasing retromer function.
The breadth of the claims encompasses neuronal cells present in both in vivo/in situ contexts and in vitro cell culture contexts.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and 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 disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claimed functional properties are dependent upon many different variable parameters, including, but not limited to:
the type of subject [parameter 1] human or non-human animal to be treated;
the type of nucleic acid vector [parameter 2];
the structure and functional properties of the VPS35, VPS26a, and/or VPS26b protein variants [parameter 3];
the structure(s) of regulatory element(s) [parameter 4];
the administration route [parameter 5];
the dosage administered [parameter 6]; and
the phenotypic response to be achieved [parameter 7].
The claims also denote that there is an amount (syn. dosage) of the nucleic acid vectors and/or one or more presently unrecited transcriptional regulatory elements operably linked to the first and second transgenes, respectively, that upon introduction into the neuronal cell, is not, in fact, effective or able to achieve the first and/or second recited functional properties, thereby increasing retromer function.
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of human and non-human animals, including mammals (pg 45, last para).
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
Parameter 2
The claimed methods are recited at a high level of generality for type of nucleic acid vector encoding the therapeutic VPS35, VPS26a, and/or VPS26b proteins, said vectors including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses (pg 22, last para), dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles (pg 9, para 2).
Parameter 3
The claimed methods are broad for reciting an enormously vast genus of structurally and functionally undisclosed:
VPS35 polypeptide variants; and/or
VPS26a polypeptide variants; and/or
VPS26b polypeptide variants.
The specification discloses (e.g. pg 4, last para) the polypeptide may have as little as 85% identity to a reference SEQ ID NO.
VPS35 SEQ ID NO:2 is 796 amino acids in length.
VPS26a SEQ ID NO:3 is 327 amino acids in length.
VPS26b SEQ ID NO:4 is 336 amino acids in length.
85% identity allows for as many as about 119 and 50 amino acid insertions, deletions, and/or substitutions anywhere within SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively.
90% identity allows for as many as about 80 and 33 amino acid insertions, deletions, and/or substitutions anywhere within SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively.
95% identity allows for as many as about 40 and 17 amino acid insertions, deletions, and/or substitutions anywhere within SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively.
20^120 = about 1x10^156 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants.
20^80 = about 1x10^104 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants.
20^50 = about 1x10^65 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants.
20^40 = about 1x10^52 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants.
20^30 = about 1x10^30 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants.
20^20 = about 1x10^26 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants.
20^10 = about 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants.
Thus, the breadth of the claims reasonably encompasses an enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants that are to have the functional property(ies) of being a retromer core protein capable of associating with endosomal organelles and control trafficking of certain cellular cargo molecules within tubular vesicular carriers to the trans Golgi network (pg 1, last para).
(www.calculator.net/exponent-calculator; last visited April 29, 2025)
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants that are to necessarily and predictably have the functional property(ies) of being a retromer core protein capable of associating with endosomal organelles and control trafficking of certain cellular cargo molecules within tubular vesicular carriers to the trans Golgi network so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic response to treat, prevent, cure, or reduce severity of a neurodegenerative disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, inhibit/retard/slow some extent of, or may stop, neurodegeneration, prevent or delay occurrence and/or recurrence of neurodegeneration, relieve to some extent one or more symptoms associated with neurodegeneration, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters, in the enormous genus of about 1x10^6 human and non-human subjects.
Parameter 4
The claims are broad for reasonably encompassing an enormous genus of structurally and functionally distinct promoters and enhancers (pg 9, para 3-4).
The Examiner notes that while the claims recite a nucleic acid encoding the VPS35, VPS26a and/or VPS26b polypeptides, the claims do not recite said nucleic acid to further comprise a promoter operably linked to said nucleic acid encoding the VPS35, VPS26a and/or VPS26b polypeptides. Thus, the claims reasonably encompass a “therapeutically effective amount” of a nucleic acid that encodes, but does not express, the VPS35, VPS26a and/or VPS26b polypeptides. See, for example, pg 9, para 3, “In some embodiments (syn. not all)…, the transgene is operably linked to a promoter that induces expression of the transgene…”.
Absent objective evidence to the contrary, it would be remedial for Applicant to amend the independent claim(s) to positively recite a promoter operably linked to the nucleic acid encoding the VPS35, VPS26a and/or VPS26b polypeptides.
Parameter 5
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes (e.g. pg 12, para 1-3), including, but not limited to, injection, infusion, orally, alimentary, ingestion, inhalation, lavage, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
Parameter 6
The claimed methods are recited at a high level of generality for the nucleic acid dosage that is to be administered, whereby the dosage may vary depending upon the age of the subject, the general condition of the subject, the severity of the condition to be treated, and the mode of administration (pg 45, last para), or the stability of the gene or RNA product, and the level of RNA expression required to achieve a therapeutic effect (pg 46, para 1).
The specification discloses a dose of about 1x10^10 to 1x10^15 rAAV genome copies/subject (pg 46, para 1), and reasonably encompasses as little as 1x10^2 to as much as 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]).
The claims are broad for encompassing an enormous genus of at least 125 different AAV capsid serotype variants, including but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV.rh10, and BAAV (DiPrimio et al (U.S. 2009/0215879; Table 3).
Parameter 7
The claims recite wherein, when the one or more vectors are introduced into the neuronal cell:
(a) the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) are increased in the neuronal cell relative to the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell, thereby increasing retromer function [function 1]; and/or
(b) the levels of Sorl1 are increased in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell [function 2],
While the specification discloses the ability to express the artisan’s transgene of interest in vitro from rAAV9 viruses (e.g. Examples 2-5), the specification and working examples are silent to in vivo delivery, let alone achieving a real-world, clinically meaningful therapeutic effect, including but not limited to treating, preventing and/or curing, the enormous genus of etiologically and pathologically distinct CNS disorders, including, but not limited to the genus recited in Claim 14, in the enormous genus of human and non-human animal subjects.
Furthermore, the in vitro working examples fail to disclose the actual dosage of AAV vectors administered to the tissue-cultured mouse neurons.
The claims fail to recite, and the specification fails to disclose, a first nucleic acid dosage [parameter 6] of a first nucleic acid vector [parameter 2], e.g. bacteriophage, encoding a first VPS35 polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35 variants, alone and/or in combination with, a second nucleic acid dosage [parameter 6] of a second nucleic acid vector [parameter 2], e.g. artificial chromosome, encoding a first VPS26a polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS26a variants, alone and/or in combination with, a third nucleic acid dosage [parameter 6] of a third nucleic acid vector [parameter 2], e.g. exosome, encoding a first VPS26b polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS26b variants administered via a first, second, and/or third administration route(s) [parameter 5], respectively, e.g. inhalation, subcutaneous, and/or orally, to a first subject [parameter 1], e.g. a rabbit, that is necessarily and predictably able to increase the levels of VPS35 and VPS26a in the neuronal cell relative to the levels of VPS35 and VPS26a when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased the Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell [function 2] [parameter 7] as opposed to
a second first nucleic acid dosage [parameter 6] of a first nucleic acid vector [parameter 2], e.g. nanoparticle, encoding a first VPS35 polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35 variants, alone and/or in combination with, a second nucleic acid dosage [parameter 6] of a second nucleic acid vector [parameter 2], e.g. artificial chromosome, encoding a first VPS26a polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS26a variants, alone and/or in combination with, a second third nucleic acid dosage [parameter 6] of a third nucleic acid vector [parameter 2], e.g. cosmid, encoding a first VPS26b polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS26b variants administered via a first, second, and/or third administration route(s) [parameter 5], respectively, e.g. intramuscularly, rectally, and/or intraperitoneally, to a second subject [parameter 1], e.g. a cow, that is necessarily and predictably able to increase the levels of VPS35 and VPS26a in the neuronal cell relative to the levels of VPS35 and VPS26a when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased the Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell [function 2] [parameter 7], for example.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial VPS35, VPS26a, and VPS26b polypeptides comprise the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, does not tell you anything at all about the structure (amino acid sequences) and functional properties of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants that are to have the functional property(ies) of being a retromer core protein capable of associating with endosomal organelles and control trafficking of certain cellular cargo molecules within tubular vesicular carriers to the trans Golgi network (pg 1, last para).
Furthermore, the claims fail to recite, and the specification fails to disclose, the nexus between:
the broad genus of structurally and functionally distinct first, second, and third nucleic acid vectors, respectively, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles, including those vectors that encode, but do not express, the VPS35, VPS26a, and/or VPS26b polypeptides;
the enormously vast genus of structurally and functionally undisclosed doses of the first, second, and third nucleic acid vectors, respectively;
the corresponding enormous genus of anatomically distinct administration routes, including, but not limited to delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic; and
the enormous genus of about 1x10^6 different animal species, respectively,
so as to necessarily and predictably achieve increased levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) in the neuronal cell relative to the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell [function 2].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants that are to have the functional property(ies) of being a retromer core protein capable of associating with endosomal organelles and control trafficking of certain cellular cargo molecules within tubular vesicular carriers to the trans Golgi network (pg 1, last para);
the broad genus of structurally and functionally distinct first, second, and third nucleic acid vectors, respectively, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles, including those vectors that encode, but do not express, the VPS35, VPS26a, and/or VPS26b polypeptides;
the enormously vast genus of structurally and functionally undisclosed doses of the first, second, and third nucleic acid vectors, respectively;
the corresponding enormous genus of anatomically distinct administration routes, including, but not limited to delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic; and
the enormous genus of about 1x10^6 different animal species, respectively,
so as to necessarily and predictably achieve increased levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) in the neuronal cell relative to the levels of VPS35 and VPS26a when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell [function 2].
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants that are to have the functional property(ies) of being a retromer core protein capable of associating with endosomal organelles and control trafficking of certain cellular cargo molecules within tubular vesicular carriers to the trans Golgi network (pg 1, last para);
the broad genus of structurally and functionally distinct first, second, and third nucleic acid vectors, respectively, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles, including those vectors that encode, but do not express, the VPS35, VPS26a, and/or VPS26b polypeptides;
the enormously vast genus of structurally and functionally undisclosed doses of the first, second, and third nucleic acid vectors, respectively;
the corresponding enormous genus of anatomically distinct administration routes, including, but not limited to delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic; and
the enormous genus of about 1x10^6 different animal species, respectively,
so as to necessarily and predictably achieve increased levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) in the neuronal cell relative to the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell [function 2], at the time the application was filed.
As discussed above, the specification discloses the ability to express the artisan’s transgene of interest in vitro from rAAV9 viruses (e.g. Examples 2-5), the specification and working examples are silent to in vivo delivery, let alone achieving a real-world, clinically meaningful therapeutic effect, including but not limited to treating, preventing and/or curing, the enormous genus of etiologically and pathologically distinct CNS disorders, including, but not limited to the genus recited in Claim 14, in the enormous genus of human and non-human animal subjects.
Furthermore, the in vitro working examples fail to disclose the actual dosage of AAV vectors administered to the tissue-cultured mouse neurons.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant argues that the amended claims render the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant claims remain deficient in the structure(s)/function(s) nexus and/or the method step(s)/function(s) nexus of the claimed limitations, including, but not limited to, elements required for the in vivo embodiments of the claimed methods.
5. Claims 3, 15, 17, 20, 22, 29, 35, 37, 40, 46, 49, and 60-66 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.
Claims 3 and 35 have been amended to recite the step of introducing into a neuronal cell at least one vector comprising:
i) a transgene encoding retromer core protein VPS35, and
ii) a transgene encoding retromer core protein VPS26a (Claim 3) or VPS26b (Claim 35) [structure],
wherein, when the one or more vectors are introduced into the neuronal cell:
(a) the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) are increased in the neuronal cell relative to the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell, thereby increasing retromer function [function 1]; and/or
(b) the levels of Sorl1 are increased in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell [function 2], thereby increasing retromer function.
The claims also denote that there is an amount (syn. dosage) of the nucleic acid vectors and/or one or more presently unrecited transcriptional regulatory elements operably linked to the first and second transgenes, respectively, that upon introduction into the neuronal cell, is not, in fact, effective or able to achieve the first and/or second recited functional properties, thereby increasing retromer function.
The breadth of the claims encompasses neuronal cells present in both in vivo/in situ contexts and in vitro cell culture contexts.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
Considering the mode of administration, the specification simply requires administration of the nucleic acid(s) to the subject by any means. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleic acid is broadly stated as being administered to a patient. The lack of guidance exacerbates the highly unpredictable field of gene therapy and the method of delivery of polynucleotides is highly unpredictable to date. Gene delivery has been a persistent problem for gene therapy protocols and the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically.
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
While the specification discloses the ability to express the artisan’s transgene of interest in vitro from rAAV9 viruses (e.g. Examples 2-5), the specification and working examples are silent to in vivo delivery, let alone achieving a real-world, clinically meaningful therapeutic effect, including but not limited to treating, preventing and/or curing, the enormous genus of etiologically and pathologically distinct CNS disorders, including, but not limited to the genus recited in Claim 14, in the enormous genus of human and non-human animal subjects.
Furthermore, the in vitro working examples fail to disclose the actual dosage of AAV vectors administered to the tissue-cultured mouse neurons.
The claims fail to recite, and the specification fails to disclose, a first nucleic acid dosage [parameter 6] of a first nucleic acid vector [parameter 2], e.g. bacteriophage, encoding a first VPS35 polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35 variants, alone and/or in combination with, a second nucleic acid dosage [parameter 6] of a second nucleic acid vector [parameter 2], e.g. artificial chromosome, encoding a first VPS26a polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS26a variants, alone and/or in combination with, a third nucleic acid dosage [parameter 6] of a third nucleic acid vector [parameter 2], e.g. exosome, encoding a first VPS26b polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS26b variants administered via a first, second, and/or third administration route(s) [parameter 5], respectively, e.g. inhalation, subcutaneous, and/or orally, to a first subject [parameter 1], e.g. a rabbit, that is necessarily and predictably able to increase the levels of VPS35 and VPS26a in the neuronal cell relative to the levels of VPS35 and VPS26a when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased the Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell [function 2] [parameter 7] as opposed to
a second first nucleic acid dosage [parameter 6] of a first nucleic acid vector [parameter 2], e.g. nanoparticle, encoding a first VPS35 polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35 variants, alone and/or in combination with, a second nucleic acid dosage [parameter 6] of a second nucleic acid vector [parameter 2], e.g. artificial chromosome, encoding a first VPS26a polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS26a variants, alone and/or in combination with, a second third nucleic acid dosage [parameter 6] of a third nucleic acid vector [parameter 2], e.g. cosmid, encoding a first VPS26b polypeptide [parameter 3] of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS26b variants administered via a first, second, and/or third administration route(s) [parameter 5], respectively, e.g. intramuscularly, rectally, and/or intraperitoneally, to a second subject [parameter 1], e.g. a cow, that is necessarily and predictably able to increase the levels of VPS35 and VPS26a in the neuronal cell relative to the levels of VPS35 and VPS26a when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased the Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell [function 2] [parameter 7], for example.
The specification fails to make up for deficiencies of the global scientific community, and thus the ordinary artisans must determine for themselves that which Applicant fails to disclose.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))), the skilled artisan would have not known how to formulate a pharmaceutical composition comprising:
the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants that are to have the functional property(ies) of being a retromer core protein capable of associating with endosomal organelles and control trafficking of certain cellular cargo molecules within tubular vesicular carriers to the trans Golgi network (pg 1, last para);
the broad genus of structurally and functionally distinct first, second, and third nucleic acid vectors, respectively, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles, including those vectors that encode, but do not express, the VPS35, VPS26a, and/or VPS26b polypeptides;
the enormously vast genus of structurally and functionally undisclosed doses of the first, second, and third nucleic acid vectors, respectively;
the corresponding enormous genus of anatomically distinct administration routes, including, but not limited to delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic;
the enormous genus of about 1x10^6 different animal species, respectively; and
the enormous genus of physiologically different therapeutic results, including but not limited to, treat, prevent, cure, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, inhibit/retard/slow some extent of, or may stop, neurodegeneration, prevent or delay occurrence and/or recurrence of neurodegeneration, relieve to some extent one or more symptoms associated with neurodegeneration, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters, so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat, prevent, and/or cure neurodegeneration.
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial VPS35, VPS26a, and VPS26b polypeptides comprise the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, does not tell you anything at all about the structure (amino acid sequences) and functional properties of the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants that are to have the functional property(ies) of being a retromer core protein capable of associating with endosomal organelles and control trafficking of certain cellular cargo molecules within tubular vesicular carriers to the trans Golgi network (pg 1, last para).
Furthermore, the claims fail to recite, and the specification fails to disclose, the nexus between:
the broad genus of structurally and functionally distinct first, second, and third nucleic acid vectors, respectively, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles, including those vectors that encode, but do not express, the VPS35, VPS26a, and/or VPS26b polypeptides;
the enormously vast genus of structurally and functionally undisclosed doses of the first, second, and third nucleic acid vectors, respectively;
the corresponding enormous genus of anatomically distinct administration routes, including, but not limited to delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic; and
the enormous genus of about 1x10^6 different animal species, respectively,
so as to necessarily and predictably achieve increased levels of VPS35 and VPS26a in the neuronal cell relative to the levels of VPS35 and VPS26a when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a has been introduced into the neuronal cell [function 2].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants that are to have the functional property(ies) of being a retromer core protein capable of associating with endosomal organelles and control trafficking of certain cellular cargo molecules within tubular vesicular carriers to the trans Golgi network (pg 1, last para);
the broad genus of structurally and functionally distinct first, second, and third nucleic acid vectors, respectively, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles, including those vectors that encode, but do not express, the VPS35, VPS26a, and/or VPS26b polypeptides;
the enormously vast genus of structurally and functionally undisclosed doses of the first, second, and third nucleic acid vectors, respectively;
the corresponding enormous genus of anatomically distinct administration routes, including, but not limited to delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic; and
the enormous genus of about 1x10^6 different animal species, respectively,
so as to necessarily and predictably achieve increased levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) in the neuronal cell relative to the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell [function 2].
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
the enormously vast genus of about 1x10^156, 1x10^104, 1x10^65, 1x10^52, 1x10^30, 1x10^26, and/or 1x10^13 structurally and functionally undisclosed VPS35, VPS26a, and/or VPS26b polypeptide variants that are to have the functional property(ies) of being a retromer core protein capable of associating with endosomal organelles and control trafficking of certain cellular cargo molecules within tubular vesicular carriers to the trans Golgi network (pg 1, last para);
the broad genus of structurally and functionally distinct first, second, and third nucleic acid vectors, respectively, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles, including those vectors that encode, but do not express, the VPS35, VPS26a, and/or VPS26b polypeptides;
the enormously vast genus of structurally and functionally undisclosed doses of the first, second, and third nucleic acid vectors, respectively;
the corresponding enormous genus of anatomically distinct administration routes, including, but not limited to delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic; and
the enormous genus of about 1x10^6 different animal species, respectively,
so as to necessarily and predictably achieve increased levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) in the neuronal cell relative to the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell, thereby increasing retromer function [function 1] and/or increased Sorl1 levels in the neuronal cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the neuronal cell [function 2], at the time the application was filed.
As discussed above, the specification discloses the ability to express the artisan’s transgene of interest in vitro from rAAV9 viruses (e.g. Examples 2-5), the specification and working examples are silent to in vivo delivery, let alone achieving a real-world, clinically meaningful therapeutic effect, including but not limited to treating, preventing and/or curing, the enormous genus of etiologically and pathologically distinct CNS disorders, including, but not limited to the genus recited in Claim 14, in the enormous genus of human and non-human animal subjects.
Furthermore, the in vitro working examples fail to disclose the actual dosage of AAV vectors administered to the tissue-cultured mouse neurons.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023; last visited September 27, 2024) s considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant argues that the amended claims render the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant claims remain deficient in the structure(s)/function(s) nexus and/or the method step(s)/function(s) nexus of the claimed limitations, including, but not limited to, elements required for the in vivo embodiments of the claimed methods.
6. Claims 37, 40, 46, 49, and 64-66 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The order of the claims is not in accordance with MPEP §608.01(m), nor complies with 35 U.S.C. 112(d).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The claims should be arranged in order of scope so that the first claim presented is the least restrictive. Claims 37, 40, 46, and 49 have been amended to recite dependency upon later presented independent Claim 63, respectively.
Applicant should correct the numbering of the claim set to comply with 35 U.S.C. 112(d) and MPEP §608.01(m).
Dependent Claims 64-66 are included in the basis of the rejection because they suffer from the deficiencies of Claim 49.
Appropriate correction is required.
See, for example, Claim 15, dependent upon Claim 3.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
7. The prior rejection of Claim(s) 15, 29, 35, and 49 under 35 U.S.C. 102(a)(1) as being anticipated by Abeliovich et al (U.S. 2016/0184454) is withdrawn in light of Applicant’s amendments to the claims to now recite a method, not a product. While Abeliovich et al disclosed a nucleic acid expression vector encoding VPS35 and/or VPS26 (e.g. [0033]; claim 54), wherein the nucleic acid vector is a viral vector [0108], wherein the viral vector may be a lentivirus, adenovirus, adeno-associated virus, or retrovirus [0194]. Abeliovich et al do not demonstrate a reduction to practice of introducing said nucleic acid expression vector encoding VPS35 and/or VPS26 into a neuronal cell.
8. Claim(s) 3 is rejected under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2) as being anticipated by Small et al (U.S. 2008/0214482; of record).
With respect to Claim 3, Small et al is considered relevant prior art for having disclosed that an in vitro method for increasing the expression of a retromer complex protein in a cell (e.g. Abstract), wherein the cell is a neuronal cell (e.g. [0088], “neuronal retromer”), e.g. brain cell, such as a pyramidal neuron (e.g. [0056, 79]), the method comprising the step(s) of introducing into said neuronal cell an expression vector encoding VPS35 and/or VPS26 (e.g. [0055-58]), thereby increasing the expression of the retromer complex proteins in the cell.
Small et al do not disclose ipsis verbis that the VPS26 is VPS26a. However, those of ordinary skill in the art previously recognized that VPS26 is synonymous with VPS26a, as shown below:
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208
494
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Small et al do not disclose ipsis verbis that co-expression of VPS35 with VPS26a resulted in increased levels of VPS35 and VPS26a in the cell relative to the levels of VPS35 and VPS26a when only a transgene encoding either VPS35 or VPS26a has been introduced into the cell, thereby increasing retromer function [function 1] and/or increased Sorl1 levels in the cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a has been introduced into the cell, thereby increasing retromer function [function 2].
Either these are inherent properties that naturally flow from the co-expression of VPS35 with VPS26a, or they are not, and something must change.
The Examiner interprets the recited functional properties to be inherent properties per natural law of cell biology.
"Products of identical chemical composition can not have mutual exclusive properties." A compound and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)). Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP §2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Small et al disclosed whereby VPS35 and VPS26 are recognized to be differentially reduced in neurodegenerative conditions such as Alzheimer’s disease (e.g. [0023-24]), whereby elevated levels of Abeta is fundamental to Alzheimer’s disease pathogenesis [0004], and whereby elevating VPS35 protein decreases Abeta levels [0027], the method comprising a nucleic acid expression vector encoding the retromer complex proteins (e.g. [0058]; claims 20 and 26), e.g. VPS35 (e.g. [0058]; claims 21 and 27) and/or VPS26 (e.g. [0058]; claim 24).
Thus, Small et al anticipate the claim.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
9. Claims 3, 15, 17, 22, 29, 35, 37, 46, 49, 60, and 63-64 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Small et al (U.S. 2008/0214482; of record) in view of Kerr et al (2005; of record), Bi et al (2013; of record), GenBank JC7516 (human VPS35; 2001; of record), GenBank AAF89954.1 (human VPS26; 2000; of record), GenBank Q4G0F5 (human VPS26B; 2006; of record), and Abeliovich et al (U.S. 2016/0184454; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 3 and 35, Small et al is considered relevant prior art for having disclosed that an in vitro method for increasing the expression of a retromer complex protein in a cell (e.g. Abstract), wherein the cell is a neuronal cell (e.g. [0088], “neuronal retromer”), e.g. brain cell, such as a pyramidal neuron (e.g. [0056, 79]), the method comprising the step(s) of introducing into said neuronal cell an expression vector encoding VPS35 and/or VPS26 (e.g. [0055-58]), thereby increasing the expression of the retromer complex proteins in the cell.
Small et al do not disclose ipsis verbis that the VPS26 is VPS26a. However, those of ordinary skill in the art previously recognized that VPS26 is synonymous with VPS26a.
Small et al do not disclose ipsis verbis that co-expression of VPS35 with VPS26a resulted in increased levels of VPS35 and VPS26a in the cell relative to the levels of VPS35 and VPS26a when only a transgene encoding either VPS35 or VPS26a has been introduced into the cell, thereby increasing retromer function [function 1] and/or increased Sorl1 levels in the cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a has been introduced into the cell, thereby increasing retromer function [function 2].
Either these are inherent properties that naturally flow from the co-expression of VPS35 with VPS26a, or they are not, and something must change.
The Examiner interprets the recited functional properties to be inherent properties per natural law of cell biology.
"Products of identical chemical composition can not have mutual exclusive properties." A compound and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)). Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP §2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Small et al disclosed whereby VPS35 and VPS26 are recognized to be differentially reduced in neurodegenerative conditions such as Alzheimer’s disease (e.g. [0023-24]), whereby elevated levels of Abeta is fundamental to Alzheimer’s disease pathogenesis [0004], and whereby elevating VPS35 protein decreases Abeta levels [0027], the method comprising a nucleic acid expression vector encoding the retromer complex proteins (e.g. [0058]; claims 20 and 26), e.g. VPS35 (e.g. [0058]; claims 21 and 27) and/or VPS26 (e.g. [0058]; claim 24).
Similarly, Kerr et al is considered relevant prior art for having taught an in vitro method of increasing retromer function in a mammalian cell culture, e.g. human HEK cells (e.g. pg 994, col. 1) or human HeLa cells (e.g. pg 995, col. 2; Figure 5), the method comprising the step(s) of introducing into said human cells one or more expression vectors encoding VPS35 and VPS26a, or VPS35 and VPS26b (e.g. Figure 5).
Kerr et al taught that the prior art recognized VPS35 naturally interacts with VPS26A as components of the retromer complex (e.g. pg 993, col. 2).
Kerr et al taught that VPS35 co-precipitated with VPS26B, confirming that VPS26B has the capacity to associate directly with the retromer complex (e.g. pg 994, col. 1).
Kerr et al do not teach ipsis verbis that co-expression of VPS35 with VPS26a (Claim 3) or VSP26b (Claim 35) resulted in increased levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) in the cell relative to the levels of VPS35 and VPS26a (Claim 3) or VPS26b (Claim 35) when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the cell, thereby increasing retromer function [function 1] and/or increased Sorl1 levels in the cell, relative to levels of Sorl1 when only a transgene encoding either VPS35 or VPS26a (Claim 3) or VPS26b (Claim 35) has been introduced into the cell, thereby increasing retromer function [function 2].
Either these are inherent properties that naturally flow from the co-expression of VPS35 with VPS26a (Claim 3) or VSP26b (Claim 35), or they are not, and something must change.
The Examiner interprets the recited functional properties to be inherent properties per natural law of cell biology.
"Products of identical chemical composition can not have mutual exclusive properties." A compound and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)). Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP §2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Kerr et al do not teach a working example whereby the host cells are neuronal host cells.
However, Kerr et al taught that VPS26b is naturally expressed in neuronal cells, e.g. the brain, eye, and dorsal root ganglion (e.g. pg 993, col. 2).
Furthermore, prior to the effective filing date of the instantly claimed invention, Bi et al is considered relevant prior art for having taught an in vitro method of expressing human VPS35 in human neuronal cells, to wit, dopaminergic neuronal N27 cells (e.g. Abstract; pg 150, col. 2), the method comprising the step of introducing into said human neuronal cells an expression vector encoding human VPS35 (e.g. Figure 1, legend).
Bi et al taught that mutations of VPS35 are present in patients suffering from Parkinson’s disease, contributing to the pathogenesis of Parkinson’s disease due to a loss of neuroprotective function (e.g. Abstract).
Bi et al taught that enhanced expression of wildtype VPS35 protects neuronal cells from toxicity caused by mitochondrial toxicants (e.g. Abstract).
Similarly, Abeliovich et al is considered relevant prior art for having disclosed a method of expressing VPS35 and/or VPS26 in mammalian cell, the method comprising the step(s) of introducing a nucleic acid expression vector encoding VPS35 and/or VPS26 (e.g. [0033]; claim 54), into said mammalian cell.
Abeliovich et al disclosed the increased expression of retromer complex proteins would be therapeutic to subjects suffering from Parkinson’s disease (e.g. [0033]).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology and gene expression vectors. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to arrive, at least, at an in vitro method of increasing retromer function in a neuronal cell comprising the step(s) of introducing into said neuronal cell one or more expression vectors encoding VPS35 in combination with VPS26a or VPS26b with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts of:
i) co-expressing VPS35 with VPS26a (Small et al, Abeliovich) or VPS26b (Kerr et al) was known and/or previously successfully reduced to practice;
ii) downregulated expression of retromer complex proteins such as VPS35 correlates with and/or is causal for neuronal diseases such as Alzheimer’s disease (Small et al) or Parkinson’s disease (Bi et al, Abeliovich); and
iii) over-expression of wildtype retromer complex proteins such as VPS35 and/or VPS26 is neuroprotective (Bi et al) and/or therapeutic for the treatment of Parkinson’s disease (Abeliovich).
Those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concepts of co-expressing VPS35 with VPS26A and/or VPS26 (Abeliovich et al; Kerr et al). The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. MPEP §2144.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 17 and 37, instant SEQ ID NO:1 encodes the human VPS35 polypeptide, and thus, absent objective evidence to the contrary, it is reasonably inferred that the wildtype human VPS35 polypeptide of Bi et al inherently and naturally comprises the amino acid sequence of instant SEQ ID NO:1.
Furthermore, GenBank JC7516 is considered relevant prior art for having taught a human VPS35 polypeptide amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO:1.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first mammalian VPS35 polypeptide, e.g. mouse or human VPS35, with a second human VPS35 polypeptide having the amino acid sequence of SEQ ID NO:1, with a reasonable expectation of success because those of ordinary skill in the art previously recognized that the human VPS35 polypeptide has the amino acid sequence of SEQ ID NO:1, and the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
With respect to Claim 22, Kerr et al taught the mouse VPS26a amino acid sequence (e.g. Figure 1, GenBank AAH07148; lower line) which is 99.5% identical (3 mismatches) to instant SEQ ID NO:2 (human VPS26a; upper line), as shown below:
MSFLGGFFGPICEIDIVLNDGETRKMAEMKTEDGKVEKHYLFYDGESVSGKVNLAFKQPG 60
|||||||||||||||: |||||||||||||||||||||||||||||||||||||||||||
MSFLGGFFGPICEIDVALNDGETRKMAEMKTEDGKVEKHYLFYDGESVSGKVNLAFKQPG 60
KRLEHQGIRIEFVGQIELFNDKSNTHEFVNLVKELALPGELTQSRSYDFEFMQVEKPYES 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
KRLEHQGIRIEFVGQIELFNDKSNTHEFVNLVKELALPGELTQSRSYDFEFMQVEKPYES 120
YIGANVRLRYFLKVTIVRRLTDLVKEYDLIVHQLATYPDVNNSIKMEVGIEDCLHIEFEY 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
YIGANVRLRYFLKVTIVRRLTDLVKEYDLIVHQLATYPDVNNSIKMEVGIEDCLHIEFEY 180
NKSKYHLKDVIVGKIYFLLVRIKIQHMELQLIKKEITGIGPSTTTETETIAKYEIMDGAP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NKSKYHLKDVIVGKIYFLLVRIKIQHMELQLIKKEITGIGPSTTTETETIAKYEIMDGAP 240
VKGESIPIRLFLAGYDPTPTMRDVNKKFSVRYFLNLVLVDEEDRRYFKQQEIILWRKAPE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
VKGESIPIRLFLAGYDPTPTMRDVNKKFSVRYFLNLVLVDEEDRRYFKQQEIILWRKAPE 300
KLRKQRTNFHQRFESPESQASAEQPEM 327
||||||||||||||||:||||||||||
KLRKQRTNFHQRFESPDSQASAEQPEM 327
Kerr et al also taught that human VPS26a was previously known (e.g. Figure 2, GenBank NP_004887) and thus, absent objective evidence to the contrary, it is reasonably inferred that the wildtype human VPS26a polypeptide inherently and naturally comprises the amino acid sequence of instant SEQ ID NO:2.
Furthermore, GenBank AAF89954.1 is considered relevant prior art for having taught a human VPS26 polypeptide amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO:2.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first mammalian VPS26a polypeptide, e.g. mouse or human VPS26a with a second human VPS26a polypeptide having the amino acid sequence of SEQ ID NO:2, with a reasonable expectation of success because those of ordinary skill in the art previously recognized that the human VPS26a polypeptide has the amino acid sequence of SEQ ID NO:2, and the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
With respect to Claim 46, Kerr et al taught the mouse VPS26b amino acid sequence (e.g. Figure 1, GenBank NP_821170; lower line) which is 99% identical (3 mismatches) to instant SEQ ID NO:3 (human VPS26b; upper line), as shown below:
MSFFGFGQSVEVEILLNDAESRKRAEHKTEDGKKEKYFLFYDGETVSGKVSLALKNPNKR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||:|||||||
MSFFGFGQSVEVEILLNDAESRKRAEHKTEDGKKEKYFLFYDGETVSGKVSLSLKNPNKR 60
LEHQGIKIEFIGQIELYYDRGNHHEFVSLVKDLARPGEITQSQAFDFEFTHVEKPYESYT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
LEHQGIKIEFIGQIELYYDRGNHHEFVSLVKDLARPGEITQSQAFDFEFTHVEKPYESYT 120
GQNVKLRYFLRATISRRLNDVVKEMDIVVHTLSTYPELNSSIKMEVGIEDCLHIEFEYNK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GQNVKLRYFLRATISRRLNDVVKEMDIVVHTLSTYPELNSSIKMEVGIEDCLHIEFEYNK 180
SKYHLKDVIVGKIYFLLVRIKIKHMEIDIIKRETTGTGPNVYHENDTIAKYEIMDGAPVR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SKYHLKDVIVGKIYFLLVRIKIKHMEIDIIKRETTGTGPNVYHENDTIAKYEIMDGAPVR 240
GESIPIRLFLAGYELTPTMRDINKKFSVRYYLNLVLIDEEERRYFKQQEVVLWRKGDIVR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GESIPIRLFLAGYELTPTMRDINKKFSVRYYLNLVLIDEEERRYFKQQEVVLWRKGDIVR 300
KSMSHQAAIA SQRFEGTTSLGEVRTPSQLSDNNCRQ 336
|||||||||||||||||||||||||| |||||| ||
KSMSHQAAIA SQRFEGTTSLGEVRTPGQLSDNNSRQ 336
Kerr et al also taught that human VPS26b was previously known (e.g. Figure 2, GenBank NP_443107) and thus, absent objective evidence to the contrary, it is reasonably inferred that the wildtype human VPS26b polypeptide inherently and naturally comprises the amino acid sequence of instant SEQ ID NO:3.
Furthermore, GenBank Q4G0F5 is considered relevant prior art for having taught a human VPS26 polypeptide amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO:3.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first mammalian VPS26b polypeptide, e.g. mouse or human VPS26b, with a second human VPS26b polypeptide having the amino acid sequence of SEQ ID NO:3, with a reasonable expectation of success because those of ordinary skill in the art previously recognized that the human VPS26b polypeptide has the amino acid sequence of SEQ ID NO:3, and the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
With respect to Claims 15, 29, 49, 60, and 63-64, Bi et al taught the viral vector is an adenovirus (e.g. pg 150, col. 2, “we chose an adenoviral system”; Figure 1A).
Abeliovich et al disclosed wherein the nucleic acid vector is a viral vector [0108], such as a lentivirus, adenovirus, adeno-associated virus, or retrovirus [0194].
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that the claimed invention yields unexpectedly improved properties not taught or suggested by the prior art, e.g. "combined VPS35 and VPS26 expression synergizes retromer function in neurons".
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that the "combined VPS35 and VPS26 expression synergizes retromer function in neurons", the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Small et al previously demonstrated the ability to co-express VPS25 and VPS26a in neuronal cells.
Similarly, Kerr et al previously demonstrated the ability to co-express VPS25 and VPS26a and/or co-express VPS25 and VPS26b in human cells, e.g. HEK or HeLa cells.
Furthermore, Applicant’s specification discloses the results were achieved in vitro neuronal cell culture using an AAV9 vector (e.g. Figures 5-6, legend), comprising at least a chicken beta actin promoter driving expression of the transgene (e.g. Example 1).
Instant independent claims are far broader in scope to asserted secondary considerations.
10. Claims 61-62 and 65-66 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Small et al (U.S. 2008/0214482; of record) in view of Kerr et al (2005; of record), Bi et al (2013; of record), GenBank JC7516 (human VPS35; 2001; of record), GenBank AAF89954.1 (human VPS26; 2000; of record), GenBank Q4G0F5 (human VPS26B; 2006; of record), and Abeliovich (U.S. 2016/0184454; of record), as applied to Claims 3, 15, 17, 22, 29, 35, 37, 46, 49, 60, and 63-64 above, and in further view of Hammond et al (Cellular selectivity of AAV serotypes for gene delivery in neurons and astrocytes by neonatal intracerebroventricular injection, PLoS One 12(12): e0188830, 22 pages, doi.org/10.1371/journal.pone.0188830, December 15, 2017).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Small et al, Kerr et al, Bi et al, nor Abeliovich teach/disclose wherein the AAV vector is an AAV2 vector (Claims 61 and 65), more specifically an AAV2/9 vector (Claims 62 and 66).
However, prior to the effective filing date of the instantly claimed invention, Hammond et al is considered relevant prior art for having taught a method of transducing neuronal cells with AAV vectors encoding the artisan’s transgene of interest, wherein the AAV vectors have capsid serotypes AAV1, AAV2, AAV8, or AAV9 (e.g. Abstract), and wherein the AAV2 vector genome is encapsidated with AAV1, AAV8, or AAV9 capsids, respectively (pg 15, last para, AAV2/1, AAV2/8, AAV2/9).
Hammond et al taught that the prior art recognized AAV9 capsids to preferentially target neurons (e.g. pg 15, para 2).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first viral vector, including, but not limited to an AAV vector, with an AAV vector comprising an AAV1, 2, 8 or 9 capsid serotype with a reasonable expectation of success because Hammond et al successfully demonstrated the ability of AAV vectors comprising an AAV1, 2, 8 or 9 capsid serotype to transduce neuronal cells, whereby the AAV vector comprises an AAV2 genome and an AAV9 capsid serotype (syn. AAV2/9), that those of ordinary skill in the art previously recognized that AAV9 capsids preferentially target neurons, and the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Citation of Relevant Prior Art
11. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Tang et al (VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function, Cell Reports 12: 1631-1643, 2015; of record) is considered relevant prior art for having an expression vector encoding wildtype mouse VPS35 or mouse VPS35 D620N mutant (e.g. pg1634, col. 1), wherein said expression vector is a plasmid.
Tang et al also taught an rAAV expression vector encoding the mouse VPS35 D620N mutant (e.g. pg1640, col. 1; pg 1641, col. 2, Methods).
Tang et al do not teach an rAAV expression vector encoding wildtype mouse VPS35.
Nevertheless, those of ordinary skill in the art previously recognized the scientific and technical concepts of expressing VPS35 from an rAAV expression vector.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art (rAAV-mutant VPS35) and the claimed invention (rAAV-wildtype VPS35) may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
Bi et al (Pathogenic Mutation in VPS35 Impairs Its Protection against MPP+ Cytotoxicity, Int. J. Biol. Sci. 9: 149-155, 2013; of record) is considered relevant prior art for having taught a viral vector encoding a human VPS35 polypeptide (e.g. pg 150, col. 1, “overexpress human VPS35… without a pathogenic mutation”; pg 150, col. 2, “we chose an adenoviral system”; Figure 1A).
With respect to Claims 17 and 37, instant SEQ ID NO:1 encodes the human VPS35 polypeptide, and thus, absent objective evidence to the contrary, it is reasonably inferred that the wildtype human VPS35 polypeptide of Bi et al inherently and naturally comprises the amino acid sequence of instant SEQ ID NO:1.
With respect to Claims 29 and 49, Bi et al taught the viral vector is an adenovirus (e.g. pg 150, col. 2, “we chose an adenoviral system”; Figure 1A).
Bi et al do not teach the viral vector to encode both VPS35 and VPS26.
Wang et al (Parkinson’s disease–associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes, Nature Medicine 22(1): 54-63, 13 pages total, 2016; of record) is considered relevant prior art for having taught a viral vector encoding a human VPS35 polypeptide (e.g. pg 54, col. 2, “human VPS35”; pg 56, col. 1, “lentivirus expressing WT human VPS35”).
With respect to Claims 17 and 37, instant SEQ ID NO:1 encodes the human VPS35 polypeptide, and thus, absent objective evidence to the contrary, it is reasonably inferred that the wildtype human VPS35 polypeptide of Wang et al inherently and naturally comprises the amino acid sequence of instant SEQ ID NO:1.
With respect to Claims 29 and 49, Wang et al taught the viral vector is a lentivirus (pg 56, col. 1, “lentivirus expressing WT human VPS35”).
Wang et al do not teach the viral vector to encode both VPS35 and VPS26.
Conclusion
12. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
Prosecution Insights