DETAILED ACTION
Election/Restrictions
Applicant's election with traverse of Groups IV, claims 23-32 and 34, HERC5 as at least one SNCA-mediated gene from claim 25, PDZRN4 as at least one SNCA-mediated gene from claim 27, neuronal cells from claim 31, and an oligonucleotide from claim 32 in the reply filed on August 12, 2025 is acknowledged. The traversal is on the ground(s) that “there is no undue burden in examining all of the claims together”.
The above arguments have been fully considered and have not been found persuasive toward the withdrawal of the restriction requirement nor persuasive toward the relaxation of same such that Groups I to V will be examined together. Although applicant argues that “there is no undue burden in examining all of the claims together”, the restriction requirement is not based on undue burden in examining all of the claims together but is dependent on Groups I to V do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features (see pages 4 and 5 of the restriction requirement mailed on February 14, 2025). Therefore, the requirement is still deemed proper and is made FINAL. In view of claims 24 and 26, and newly added claims 35-37, the examiner called Mr. James Klobucar (Reg. No. 67,860) on October 28, 2025 and asked whether he could select a species from claims 24 and 26, an oligonucleotide from claims 35 and 37, and an oligonucleotide from claim 36. During a telephone conversation, a provisional election was made without traverse to prosecute a species in claim 24, SEQ ID NO: 4 in claims 35 and 37, and a phosphorothioate oligonucleotide in claim 36. Affirmation of this election must be made by applicant in replying to this Office action. Claims 26 and 27 has been withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention since claim 27 is dependent on claim 26. Claims 23-25, 28-32, and 35-37 will be examined.
Claim Objections
Claim 23 is objected to because of the following informality: “SNCA” is an abbreviation. It only can be used after the whole phrase representing the abbreviation appears once.
Claim 24 is objected to because of the following informality: “a molecule” should be “the molecule”.
Claim 25 is objected to because of the following informality: “at least one of HERCS or HERC6” should be “at least one of HERCS and HERC6”.
Appropriate correction is required.
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.
Scope of Enablement
Claims 23-25, 28-32, and 35-37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for measuring the expression of, or the activity of a gene expression product encoded by SNCA gene in cells having a SNCA genomic variant, does not reasonably provide enablement for detecting a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene in response to a molecule using the methods recited in claims 23-25, 28-32, and 35-37. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The Nature of The Invention
The claims are drawn to a method for detecting a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene in response to a molecule. The invention is a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The Breadth of The Claims
Claims 23-25, 28-32, and 35-37 encompass a method for detecting a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene comprising: measuring the expression of, or the activity of a gene expression product encoded by a SNCA-mediated gene in cells having a SNCA genomic variant and detecting a change in the expression of or an activity in response to any kind of molecule, wherein the change detected comprises a change in the synthesis of a gene expression product, an activity of the gene expression product or the expression of an mRNA encoded by the SNCA-mediated gene. Claim 32 further limits claim 23 and requires that the molecule is an oligonucleotide.
Working Examples
The specification provides examples (see pages 18-28 of US 2022/0325346 A1, which is US publication of this instant case). However, the specification provides no working example for detecting a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene in response to a molecule using the methods recited in claims 23-25, 28-32, and 35-37.
The Amount of Direction or Guidance Provided and The State of The Prior Art
Although the specification provides examples (see pages 18-28 of US 2022/0325346 A1, which is US publication of this instant case), the specification provides no working example for detecting a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene in response to a molecule using the methods recited in claims 23-25, 28-32, and 35-37. Furthermore, there is no experimental condition and/or experimental data in the specification to support the claimed invention. During the process of the prior art search, the examiner has not found any prior art which is related to detect a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene in response to a molecule using the methods recited in claims 23-25, 28-32, and 35-37.
Level of Skill in The Art, The Unpredictability of The Art, and The Quantity of Experimentation Necessary
While the relative skill in the art is very high (the Ph.D. degree with laboratory experience), there is no predictability whether a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene in response to a molecule can be detected using the methods recited in claims 23-25, 28-32, and 35-37.
The specification teaches that “[T]he molecule of the invention can be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it can be enclosed in hard or soft shell gelatin capsules, or it can be compressed into tablets, or it can be incorporated directly with the food of the diet”, “[T]he molecule of the invention can also be administered parenterally”, “[T]he molecule of the invention can also be administered directly to the brain using stereotactic surgery”, and “[T]he molecule of the invention can also be delivered by a viral vector” (see paragraphs [0130], [0132], [0136], and [0137] of US 2022/0325346 A1, which is US publication of this instant case). Although claim 23 requires detecting a change in the expression of or an activity in response to a molecule and claim 32 requires that the molecule is an oligonucleotide, since claim 23 does not indicate how the molecule enters to cells having a SNCA genomic variant and interacts with or modulates an SNCA-mediated gene in the cells having a SNCA genomic variant and does not require to compare expression of, or an activity of a gene expression product encoded by the SNCA-mediated gene in the presence of the molecule and expression of, or an activity of a gene expression product encoded by the SNCA-mediated gene in the absence of the molecule, it is unpredictable how a change in the expression of, or an activity of a gene expression product encoded by the SNCA-mediated gene in response to the molecule can be detected using the methods recited in claims 23-25, 28-32, and 35-37. Furthermore, although the specification teaches that “[T]he oligonucleotide sequence of SEQ ID NO:4 is GTGGTGCATGGTGTGACA ACAGTGGCTGAG corresponding to SNCA genomic variant rs104893877 (A53T)”, “[V]ariant rs104893877 (A53T) also increases binding site affinity for MAG, TBX4/5, MEIS1 which also regulate HERC3, HERC5, HERC6, SPARCL1, ABCG2 and PPMK1 and MMRN1 in cis and PDZRN4 in trans”, and “[T]he HERC5 promoter displays a binding site for TBX5. An increased score of the binding motif for this transcription factor is created by the SNCA genomic variant rs104893877 (A53T). A SREBF1/SREBP1 site was identified in the HERC5 promoter. The JASPAR analysis found several high scoring binding motifs for KLF4 and 5, NFIX and at least one high scoring binding motif for Pax2 within the HERC5 gene's 5’ DNA sequence. HERC5 expression is regulated through a transcription factor binding motif created by the SNCA genomic variant rs104893877 (A53T)” (paragraphs [0030], [0078], and [0206] of US 2022/0325346 A1, which is US publication of this instant case) and it is known that the HERC3, 5, and 6 genes are located near SNCA and entangled with the SNCA-triplication cohort (see Figure 1 and page 5, left column from Prehl et al., Frontiers in neuroscience, 16, Article 889802, 2022), since claims 24 and 25 do not indicate that a SNCA genomic variant is SNCA genomic variant rs104893877 and the specification does not teach that the expression of HERC5 mRNA or an activity of HERC5 protein in cells having any kind of SNCA genomic variant increases in response to any kind of molecule such as any kind of oligonucleotide and HERC5 expression is regulated through a transcription factor binding motif created by the SNCA genomic variant rs104893877 (A53T) by what kind of mechanism, it is unpredictable how the expression of, or an activity of a gene expression product encoded by, the SNCA-mediated gene such as HERC5 gene can increase in response to any kind of molecule as recited in claims 24 and 25. In addition, although the specification teaches that “[T]he present invention discloses that several SNCA-mediated genes can be placed in the non-canonical Notch pathway through their functions in endocytic trafficking, ligand binding and mitochondrial action. These genes include ABCG2, PPM1K, HERC3, HERC5, HERC6 and PDZRN4. Moreover, PD-associated mutations and some of the SNCA-mediated genes affecting intracellular routing of the Notch receptor are systematically associated with Lewy bodies”, “[T]he present invention discloses an analysis of SNCA-mediated genes and determined that seven of these genes are directly linked to the Notch activation pathway, namely ABCG2, PPM1K, HERC3, HERC5, HERC6, SPARCL1 and PDZRN4”, “[N]on-canonical Notch pathway regulates cell survival through activation of mechanistic target of rapamycin complex 2 (mTORC2)/Akt signaling. Dysregulation of PPM1K affects mitochondrial permeability and thus impedes Akt/Pink1/mTORC2 activation. These and other known biological activities of PPM1K can be employed by those skilled in the art to design screening assays to screen for test compounds that modulate these activities, thereby identifying potential therapeutic agents for the treatment of PD”, and “[N]otch pathway specific interference (HERC3, HERC5, HERC6): The HERC3, HERC5 and HERC6 genes lie 1.35, 1.27 and 1.2 Mb, respectively, upstream from SNCA on chromosome 4. The expression of HERC3, HERC5 and HERC6 in PD neurons is regulated by the transcriptional enhancer activity of SNCA genomic variants” (see paragraphs [0089], [0154], [0158], and [0159] of US 2022/0325346 A1, which is US publication of this instant case), since claim 28 does not indicate how a SNCA-medicated gene such as HERC5 gene is correlated with phosphor-Ser473-Akt or Notch and the specification does not teach that the expression of HERC5 in any kind of cells is regulated by the transcriptional enhancer activity of any kind of SNCA genomic variant, it is unpredictable how the change in expression of, or the activity of a gene expression product encoded by the SNCA-mediated gene such as HERC5 gene can be detected by a change in the amount of phospho-Ser473-Akt or Notch as recited in claim 28. Since it is known that no association of SNP rs356165 in SNCA gene with Parkinson’s disease in Chinese population (see abstract from Hu et al., Neuroscience Letters, 479, 1, 31-33, 2010), claims 23 and 29 do not indicate that the molecule is what kind of molecule, the molecule causes what kind of change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene such as HERC5 gene, and where the mutation of a SNCA genomic variant is located, if the cells having the SNCA genomic variant are from the Chinese population, it is unpredictable how the molecule can be potentially useful for treating or preventing the progression of Parkinson’s disease (PD) in a carrier of any kind of SNCA genomic variant such as SNCA genomic variant rs356165 wherein the carrier is a Chinese subject.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art”. The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genentech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “[I]t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement”.
In view of above discussions, the skilled artisan will have no way to predict the experimental results. Accordingly, it is concluded that undue experimentation is required to make the invention as it is claimed. These undue experimentation at least includes to test whether a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene in response to a molecule can be detected using the methods recited in claims 23-25, 28-32, and 35-37.
Conclusion
In the instant case, as discussed above, the level of unpredictability in the art is high, the specification provides one with no guidance that leads one to claimed methods. One of skill in the art cannot readily anticipate the effect of a change within the subject matter to which the claimed invention pertains. Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of any working example related to claimed invention and the no teaching in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 23-25, 28-32, and 35-37 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 23 is rejected as vague and indefinite because it is unclear that a change in the expression of or an activity of what in response to a molecule is detected. Please clarify.
Claim 34 recites the limitation “the assay” in the claim. There is insufficient antecedent basis for this limitation in the claim because there is no word “assay” in claim 23. Please clarify.
Claim 36 recites the limitation “the nucleotide” in the claim. There is insufficient antecedent basis for this limitation in the claim because there is no word “nucleotide” in claim 23 or 32. Please clarify.
Claim Rejections - 35 USC § 102
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.
Claims 23, 24, 30, 32, and 34 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Mak et al., (US 2015/0037257 A1, published on February 5, 2015).
Regarding claims 23, 24, 30, 32, and 34, since the specification defines a set of genes connected to Parkinson’s disease as “SNCA-mediated genes” (see paragraph [0002]), α-synuclein (SNCA) gene can be considered as a SNCA-mediated gene. Thus, Mak et al., teach a method for detecting a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene comprising: measuring the expression of, or the activity of a gene expression product encoded by a SNCA-mediated gene (ie., SNCA gene) in cells having a SNCA genomic variant (ie., the human test-subject SNCA-Tri fibroblasts) and detecting a change in the expression of or an activity in response to a molecule (ie., herbicide paraquat (PO)), wherein the change detected comprises a change in the synthesis of a gene expression product, an activity of the gene expression product or the expression of an mRNA encoded by the SNCA-mediated gene (ie., 7.5 fold increase in SNCA mRNA) as recited in claim 23 wherein the expression of, or an activity of a gene expression product encoded by the SNCA-mediated gene increases in response to the molecule as recited in claim 24, the cells are human cells as recited in claim 30, the molecule is a small molecule (ie., PO) as recited in claim 32, and the method is a cell-based assay for detecting the change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene (ie., SNCA gene) as recited in claim 34 (see paragraphs [0090] to [0094]).
Therefore, Mak et al., teach all limitations recited in claims 23, 24, 30, 32, and 34.
Claims 23, 29-32, and 34 are rejected under 35 U.S.C. 102 (a) (2) as being anticipated by Chiba-Falek et al., (US 2021/0189361A1, priority date: April 23, 2018).
Regarding claims 23, 29-32, and 34, since the specification defines a set of genes connected to Parkinson’s disease as “SNCA-mediated genes” (see paragraph [0002]), α-synuclein (SNCA) gene can be considered as a SNCA-mediated gene. Thus, Chiba-Falek et al., teach a method for detecting a change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene comprising: measuring the expression of, or the activity of a gene expression product encoded by a SNCA-mediated gene (ie., SNCA gene) in cells having a SNCA genomic variant (ie., hiPSC line derived from a patient with SNCA triplication (SNCA-Tri) that was differentiated into dopaminergic progenitor neurons (MD NPC), the primarily neuronal type affected in PD) and detecting a change in the expression of or an activity in response to a molecule (ie., a lentiviral vector comprising gRNA4-dCas9-DNMT3A expression cassette), wherein the change detected comprises a change in the synthesis of a gene expression product, an activity of the gene expression product or the expression of an mRNA encoded by the SNCA-mediated gene (ie., decreasing the expression of SNCA mRNA or α-synuclein protein) as recited in claim 23 wherein the molecule is potentially useful for treating or preventing the progression of Parkinson’s disease (PD) in a carrier of a SNCA genomic variant (ie., by decreasing the expression of SNCA mRNA or α-synuclein protein) as recited in claim 29, the cells are human cells as recited in claim 30, the cells are neuronal cells, neuronal progenitor cells, differentiated neurons or oligodendrocytes as recited in claim 31, the molecule is an oligonucleotide (ie., a lentiviral vector comprising gRNA4-dCas9-DNMT3A expression cassette) as recited in claim 32, and the method is a cell-based assay for detecting the change in the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene (ie., SNCA gene) as recited in claim 34 (see paragraphs [0019] and [0022], Examples 3 and 4 in pages 21 and 22, and Figures 1B and 4A to 4C).
Therefore, Chiba-Falek et al., teach all limitations recited in claims 23, 29-32, and 34.
Conclusion
No claim is allowed.
Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center. The faxing of such papers must conform with the notices published in the Official Gazette, 1096 OG 30 (November 15, 1988), 1156 OG 61 (November 16, 1993), and 1157 OG 94 (December 28, 1993)(See 37 CAR § 1.6(d)). The CM Fax Center number is (571)273-8300.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph.D., whose telephone number is (571)272-0746. The examiner can normally be reached on Monday-Friday from 9 A.M. to 5 P.M.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Dr. Anne Gussow, Ph.D., can be reached on (571)272-6047.
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/FRANK W LU/Primary Examiner, Art Unit 1683 November 13, 2025