DETAILED ACTION
Response to Amendment
Applicant’s response to the office action filed on Mary 14, 2026 have been entered. The claims pending in this application are claims 1-17, 19, 20, and 22-37 wherein claims 1-17, 19, 20, 22, 26, 27, and 33 have been withdrawn due to the restriction requirement mailed on February 14, 2025. The objections and rejections not reiterated from the previous office action are hereby withdrawn in view of applicant’s amendment filed on May 14, 2026. Claims 23-25, 28-32, and 34-37 and HERC5 in claim 25 will be examined.
Claim Objections
Claim 23 is objected to because of the following informalities: (1) “a synuclein alpha-mediated (SNCA-mediated) gene” in the preamble should be “an alpha synuclein-mediated (SNCA-mediated) gene”; (2) “a gene expression product encoded by, a SNCA-mediated gene in cells having a SNCA genomic variant” in second measuring step should be “the gene expression product encoded by, the SNCA-mediated gene in the cells having the SNCA genomic variant”; and (3) “detecting a change in response to the molecule comparing the expression of, or the activity of a gene expression product encoded by, a SNCA-mediated gene in cells having a SNCA genomic variant with and without a molecule” in detecting step should be “detecting a the change in response to the molecule comparing the expression of, or the activity of the gene expression product encoded by, the SNCA-mediated gene in the cells having the SNCA genomic variant with and without the molecule”.
Claim 25 is objected to because of the following informality: “at least one of HERC5 or HERC6” should be “at least one of HERC5 and HERC6”.
Response to Arguments
In page 9, second and third paragraphs of applicant’s remarks, applicant argues that “[A]pplicant further believes that the use of the term ‘or’ is more correct than the use of the term ‘and’ as the word ‘and’ is sometimes interpreted to mean that both HERC5 and HERC6 must be present, whereas the use of the term “or’ is interpreted to mean ‘and/or’ allowing for one or the other or both”.
The above argument has been fully considered but it is not persuasive toward the withdrawal of rejection because the word “or” and the word “and” have different meaning, the word “or’ cannot be interpreted to mean “and”. Since the phrase “at least one” in claim 25 can mean one or more than one, the phrase “at least one of HERC5 and HERC6” is correct.
Claim 29 is objected to because of the following informality: “a SNCA genomic variant” should be “the SNCA genomic variant”.
Claim 34 is objected to because of the following informality: “an activity of the gene expression product encoded by, a SNCA-mediated gene” should be “the activity of the gene expression product encoded by the SNCA-mediated gene”.
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
Note that this rejection is modified from the rejection mailed on November 18, 2025 in view of the amendment filed on May 14, 2026 wherein a SNCA gene in claim 23 is not considered as a SNCA mediated gene.
Claims 23-25, 28-32, and 34-37 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 a SNCA-mediated gene in cells having a SNCA genomic variant without a molecule in vitro, 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 any kind of molecule in vivo by comparing the expression of, or the activity of the gene expression product encoded by the SNCA-mediated gene in the cells having any kind of SNCA genomic variant with and without the molecule using the methods recited in claims 23-25, 28-32, and 34-37. 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 the expression of, or an activity of a gene expression product encoded by a SNCA-mediated gene in vivo 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 34-37 encompass a method for detecting a change in the expression of, or an activity of a gene expression product encoded by, a synuclein alpha-mediated (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 any kind of SNCA genomic variant without any kind of molecule and measuring the expression of, or the activity of a gene expression product encoded by, the SNCA-mediated gene in the cells having the SNCA genomic variant with the molecule, thereby detecting the change in response to the molecule by comparing the expression of, or the activity of the gene expression product encoded by the SNCA-mediated gene in the cells having the SNCA genomic variant with and without the 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.
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 any kind of molecule in vivo by comparing the expression of, or the activity of the gene expression product encoded by the SNCA-mediated gene in the cells having any kind of SNCA genomic variant with and without the molecule using the methods recited in claims 23-25, 28-32, and 34-37.
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 any kind of molecule in vivo by comparing the expression of, or the activity of the gene expression product encoded by the SNCA-mediated gene in the cells having any kind of SNCA genomic variant with and without the molecule using the methods recited in claims 23-25, 28-32, and 34-37. 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 any kind of molecule in vivo by comparing the expression of, or the activity of the gene expression product encoded by the SNCA-mediated gene in the cells having any kind of SNCA genomic variant with and without the molecule using the methods recited in claims 23-25, 28-32, and 34-37 when the SNCA gene is not considered as a SNCA mediated gene.
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 any kind of molecule in vivo by comparing the expression of, or the activity of the gene expression product encoded by the SNCA-mediated gene in the cells having any kind of SNCA genomic variant with and without the molecule can be detected using the methods recited in claims 23-25, 28-32, and 34-37.
First, since the specification shows that “the terms ‘molecule’ and ‘compound’ are used interchangeably herein and refers to any molecule known to one skilled in the art, such as, but not limited to, small molecules, oligonucleotides (including short interfering RNAs and aptamers), peptides, polypeptides (including aptamers, zinc fingers and fragments thereof), proteins (including antibodies and fragments thereof) as well as derivatives or modified forms thereof. In some embodiments, a molecule is delivered using a viral vector”, “[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. For oral therapeutic administration, the molecule of the invention may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like”, “[T]he molecule of the invention can also be administered parenterally”, and “[T]he molecule of the invention can also be administered directly to the brain using stereotactic surgery” (see paragraphs [0020], [0130], [0132], [0136], and [0137] of US 2022/0325346 A1, which is US publication of this instant case), claims 23-25, 28-31 and 34
does not limit a molecule to a specific molecule and 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 with the molecule in claim 23 requires to deliver the molecule to the cells having a SNCA genomic variant in vitro or in vivo. Since the molecule in claim 23 can be any kind of molecule such as a nucleic acid and the cells in claim 23 can be any kind of cell, the process for delivering the molecule such as the nucleic acid to the cells having a SNCA genomic variant in claim 23 can be reasonably considered to be performed by gene transfer via various administration routes in vivo. The administration route includes subcutaneous, intravenous, intramuscular, intrathecal, intraperitoneal, oral, topical, dermal, transdermal, inhalation, and intranasal administration etc. The nucleic acid can be in a vector. The vector containing the nucleic acid can be a plasmid, a retrovirus vector, an adenovirus vector, an AAV vector or other type of vector. The state of the prior art of nucleic acid transfer was not well developed and was highly unpredictable before the effective filing date of the claimed invention. While progress has been made in recent years for nucleic acid transfer in vivo, vector targeting to desired tissues in vivo continues to be unpredictable and inefficient as supported by numerous teachings available in the art. There are many factors that contribute to the unpredictability of gene transfer in vivo.
Kotterman et al., (Nature Reviews, 15, 445-451, 2014) reports that AAV still has significant challenges regarding successful use in gene delivery and payload (page 450, middle column). Specifically Kotterman et al., point out that “[T]he immune system is highly effective at preventing the delivery of foreign nucleic acids, thereby posing many challenges to therapeutic gene delivery. The majority of the human population has been naturally exposed to adeno-associated viruses (AAVs), and natural AAV variants and serotypes show considerable sequence identity”, “widespread natural exposure to AAVs has resulted in a large portion of the population with neutralizing antibodies specific to capsids in the blood and other body fluids, which markedly limit gene delivery by many natural vectors... following cellular transduction, AAV capsid epitopes can become cross-presented on major histocompatibility complex (MHC) class I molecules, which leads to the elimination of transduced cells by capsid- specific cytotoxic T lymphocytes and the corresponding loss of gene expression”, “[F]or systemically administered viruses, the liver is often the default destination, which can represent a barrier when other organs are the intended targets. In addition, endothelial cell layers, especially those within the blood-brain barrier, pose a physical barrier for entry into a tissue. A vector that gains access to an organ, or that is directly administered to that organ, can then encounter numerous transport barriers to efficient transduction of the often large tissue volumes involved in disease, including cell bodies and intervening extracellular matrix to which many AAV variants bind”, and “[T]he surface of a target cell may lack the primary and/or secondary receptors that are necessary for vector binding and internalization. Furthermore, endosomeal escape, proteasomal escape, nuclear entry and vector unpackaging all represent barriers to transduction” (e.g. see page 447, BOX 1).
Shim et al., (Current Gene Therapy, 18, 3-20, 2018) reports that in all gene therapy applications, delivery issues are essential, and nucleic acids are highly polar macromolecules and cannot diffuse through cell membranes. For or the delivery of nucleic acids into target cells, viral and nonviral methods have been used. Despite success, viral vectors still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems. “[A]lthough nonviral methods have many advantages, including safety, the reasons these methods are falling behind viral methods with regard to outcomes might still be a matter of ‘delivery’, including passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release... Behavior in the physiological environment is the most important hurdle for vectors” (e.g., see page 3, right column, second paragraph and page 15, left column, fourth paragraph). Thus, viral vector delivery of nucleic acid still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems. Nonviral delivery of nucleic acid still face the hurdle of passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release.
Lenzi et al., (NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington (DC): National Academies Press (US), pages 1-16, 2014) discuss scientific hurdles of gene transfer in vivo. Some scientific hurdles, such as the absence of efficient delivery systems, difficulty with sustained expression, insertional mutagenesis and host immune reactions, remain formidable challenges to the field of gene transfer. Many of the hurdles have to do with providing efficient gene delivery. For examples, the vector uptake and distribution must be tightly controlled so that expression of the vector-encoded gene remains within the therapeutic range-if the expression is too low, the functional protein product may not be produced at a high enough concentration to effectively restore the intended biochemical pathway. Transcription of the new genetic material must remain stable. The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. The ideal vector would be cell-type specific, but the design of either non-viral or viral vectors that successfully target a specific cellular receptor has been elusive despite a great deal of effort. To date, re-engineered viral vectors are often too large, too unstable, or otherwise unable to reach the nucleus of some cell types. Non-viral gene delivery remains prohibitively inefficient for most therapeutic applications (e.g., see page 10, under “Scientific Hurdles”). For viral vectors, especially adenoviral and adeno-associated viral vectors, the exposed individuals have circulating antibodies that can interfere with transduction of closely related recombinant vectors. The control of an unanticipated immune response can be complicated by the challenge of “turning off” expression of transgene driven by constitutive, non-conditioned promoter sequence specifically designed to always be “on” (e.g., see page 11, first paragraph).
In view of above discussions, the degree to which the vector containing the transgene is taken up in sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. Administration routes also play an important role to determine whether sufficient vector can be obtained at target sites in a subject. Different administration route of the nucleic acid can result in different efficiency of gene expression and can influence whether sufficient expressed gene product can be obtained at the target cells so as to perform its purpose in vivo. The type of promoter used also can affect the efficiency of desired nucleic acid and gene product expressed at the target cells and whether sufficient nucleic acid and gene product is expressed so as to provide desired effect in vivo. Since claims 23-25, 28-31, and 34 do not indicate that the cells having a SNCA genomic variant are located in which part of a subject and how the molecule such as the nucleic acid is entered to the body of a subject and contacted with at least cell in vivo, it is unpredictable how the expression of, or the activity of a gene expression product encoded by a SNCA-mediated gene in cells having a SNCA genomic variant with the molecule can be measured such that 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 such as the nucleic acid in vivo by comparing the expression of, or the activity of a gene expression product encoded by the SNCA-mediated gene in cells having the SNCA genomic variant with and without the molecule such as the nucleic acid as recited in claims 23-25, 28-31, and 34 cannot be detected.
Second, since applicant has elected an oligonucleotide in claim 32 for the examination, claim 35 requires that is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, their complementary sequences, reverse sequences, or reverse complementary sequences, and claim 37 requires that the oligonucleotide is a subsequence or a segment of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5, wherein the oligonucleotide is 11 to 30 nucleotides in length comprising the subsequence or the segment of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5, the process for delivering the molecule such as the oligonucleotide to the cells having a SNCA genomic variant recited in claims 32 and 35-37 can be reasonably considered to be performed by oligonucleotide transfer via various administration routes in vivo. The administration route includes subcutaneous, intravenous, intramuscular, intrathecal, intraperitoneal, oral, topical, dermal, transdermal, inhalation, and intranasal administration etc. Since it is known that oligonucleotides are unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need to be delivered intrathecally to the central nervous system (CNS) (see abstract from Barker et al., Sci. Transl. Med., 17, erdi2245, 2024), claim 31 requires that the cells are neuronal cells, neuronal progenitor cells, differentiated neurons or oligodendrocytes, and claims 32 and 35-37 do not indicate that the cells are specific cells and the oligonucleotide is delivered to the cells by which administration route, if the cells are neuronal cells, neuronal progenitor cells, differentiated neurons or oligodendrocytes from central nervous system (CNS) and the oligonucleotide is delivered to the neuronal cells, neuronal progenitor cells, differentiated neurons or oligodendrocytes from central nervous system (CNS) of a mammal by intravenous administration, it is unpredictable how the oligonucleotide can cross the blood-brain barrier (BBB) of the mammal and can be delivered to the cells such as neuronal cells, neuronal progenitor cells, differentiated neurons or oligodendrocytes from central nervous system (CNS) of the mammal by intravenous administration such that the expression of, or the activity of a gene expression product encoded by a SNCA-mediated gene in cells having a SNCA genomic variant with the molecule such as the oligonucleotide cannot be measured and 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 such as the oligonucleotide in vivo by comparing the expression of, or the activity of a gene expression product encoded by the SNCA-mediated gene in the cells having the SNCA genomic variant with and without the molecule such as the oligonucleotide as recited in claims 31, 32 and 35-37 cannot be detected.
Third, 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 claim 24 does not require that the SNCA-mediated gene is a specific gene, the molecule is a specific molecule, and the SNCA genomic variant is a specific SNCA genomic variant, 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, 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 such as any kind of oligonucleotide as recited in claims 24 and 25. Furthermore, 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]o 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 in cells having any kind of SNCA genomic variant is correlated with phosphor-Ser473-Akt or Notch, 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. In addition, 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 having 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 any kind of molecule in vivo by comparing the expression of, or the activity of the gene expression product encoded by the SNCA-mediated gene in the cells having any kind of SNCA genomic variant with and without the molecule can be detected using the methods recited in claims 23-25, 28-32, and 34-37.
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.
Response to Arguments
In page 9, fourth paragraph bridging to page 13, second paragraph of applicant’s remarks, applicant argues that applicant has amended instant claim 23 “to recite that the method for detecting a change in the expression of, or an activity of a gene expression product encoded by, a synuclein alpha-mediated (SNCA-mediated) gene involves testing for the SNCA-mediated in the absence of the molecule (which the Examiner indicates is enabled) in order to get a baseline, and then subsequently testing in the presence of the molecule in order to ascertain the change in expression of the gene or a gene expression product due to the presence of the molecule. Simply by finding the difference between the two expression levels, one is able to ascertain a change in the expression of, or an activity of a gene expression product encoded by, a synuclein alpha-mediated (SNCA-mediated) gene. The addition of a molecule to the assay, which is described on page 65 in paragraph [0201] of the written description, and the subsequent paragraphs [0202] et seq. with results of expression levels of various genes that are SNCA-mediated genes demonstrates that one can ascertain the expression levels by following the protocol set out in paragraph [0201] of the written description. This indicates that expression levels can be determined without undue experimentation by following these teachings. Applicant notes that the Examiner also rejects claim 23 under 35 USC 102 as being anticipated using Mak (US Patent Application Publication 2015/0037257 A1), which will be addressed infra. Of note, if a prior art publication (i.e., Mak) can be used to reject independent claim 23 for novelty, Applicant submits that claim 23 must be enabled because only an enabled reference can be used to reject a claim under 35 USC 102 (see, for example, Elan Pharm., Inc. V. Mayo Found. For Med. Educ. & Research, 346 F.3d 1051 (Fed. Cir. 2003) and MPEP 2121.01. Applicant notes that if Mak is enabled, then present claim 23 must also be enabled. To the extent that the Examiner alleges that the specification does not provide sufficient information to enable the claims by including a molecule, Applicant notes that ‘A patent need not teach, and preferably omits, what is well known in the art.’ See In re Buchner, 929 F.2d 660, 661, (Fed. Cir. 1991). If Mak is enabled for disclosing a molecule to ascertain a difference in expression levels, then the present claim 23 must also necessarily be enabled. Regarding the Wands factors, Applicant submits that by following the teachings of the written description, and in particular, the paragraph [0201] on page 65 means that the quantity of experimentation necessary is not undue as one could simply follow the same protocol with a sole change being the addition of a molecule. By ascertaining a difference in the assay in the absence of the molecule with the results from the assay in the presence of the molecule would allow one to ascertain the expression differences without undue experimentation. Similarly, following the teaching in the paragraph [0201] on page 65 provides sufficient guidance so that the amount of direction or guidance presented is not undue. Applicant has shown in paragraphs [0202] et seq. examples of SNCA-mediated genes and their expression levels, meaning that the present application possesses the presence of working examples. A minor modification by assessing the expression levels of these same genes in the presence of a molecule is not beyond the scope of one skilled in the art (particularly because the skill level in the art is high), and the amount of experimentation would not be undue. Regarding the nature of the invention, Applicant notes that instant claim 23 is directed to determining expression levels of SNCA-mediated genes. In light of the fact that Applicant has shown how these expression levels can be determined, the Nature of the invention has been defined in the claim SO that practicing it is not undue. Applicant notes that the state of the prior art is such that the Examiner has presented a reference (i.e., Mak) which allegedly anticipates the instant invention. Accordingly, in light of this reference, the state of the prior art is such that the instant invention is not significantly different from the prior art so that the present invention can be practiced without undue experimentation. In biotech inventions (like the present invention), the relative skill of those in the art is acknowledged to be high. Applicant notes that in biotech inventions, there tends to be some unpredictability in practicing the invention. However, in light of the extensive experimental protocol disclosed in paragraphs [0201] and the paragraphs that follow, this cannot be considered to be undue. Finally, the breadth of the claims are not overly broad so that one of skill in the art (wherein the skill level is acknowledged to be high) could practice the claims by following the teachings in the written description. Accordingly, Applicant submits that in light of weighing of the various Wands factors, one should come to the conclusion that the instant claims are enabled for their full recited scope. Applicant notes that there is also abundant disclosure in the written description about how a molecule can be administered and expression levels measured. To wit, Applicant notes that the word ‘molecule’ appears 125 times in the written description, and most of these mentions relate to how the molecule can be administered (e.g., using a viral vector as disclosed in paragraph [0020] or a cell penetrating peptide, or encoded by an expression vector as disclosed in paragraph [0115], or orally administered as disclosed in paragraph [0130], or parenterally administered as disclosed in paragraph [0132], or stereotactic surgery as disclosed at paragraph [0136]), the nature of the molecule (e.g., what types of molecules can be administered), and/or how they modulate gene expression. In light of the abundant description about how a molecule can be administered, the abundant disclosure on how one would test in the absence and presence of a molecule to ascertain a difference in expression levels for SNCA- mediated genes (see paragraphs [0016] and [0166]), and the examples that have been shown (see paragraphs [0201] et seq.), Applicant believes that full scope of claims 23-25, 28-32, and 35-37 can be practiced without undue experimentation. The rejection is inapposite”.
The above arguments have been fully considered but they are not persuasive toward the withdrawal of rejection.
First, although applicant argues that “[T]he addition of a molecule to the assay, which is described on page 65 in paragraph [0201] of the written description, and the subsequent paragraphs [0202] et seq. with results of expression levels of various genes that are SNCA-mediated genes demonstrates that one can ascertain the expression levels by following the protocol set out in paragraph [0201] of the written description. This indicates that expression levels can be determined without undue experimentation by following these teachings”, “[R]egarding the Wands factors, Applicant submits that by following the teachings of the written description, and in particular, the paragraph [0201] on page 65 means that the quantity of experimentation necessary is not undue as one could simply follow the same protocol with a sole change being the addition of a molecule. By ascertaining a difference in the assay in the absence of the molecule with the results from the assay in the presence of the molecule would allow one to ascertain the expression differences without undue experimentation. Similarly, following the teaching in the paragraph [0201] on page 65 provides sufficient guidance so that the amount of direction or guidance presented is not undue. Applicant has shown in paragraphs [0202] et seq. examples of SNCA-mediated genes and their expression levels, meaning that the present application possesses the presence of working examples”, and “[I]n light of the abundant description about how a molecule can be administered, the abundant disclosure on how one would test in the absence and presence of a molecule to ascertain a difference in expression levels for SNCA- mediated genes (see paragraphs [0016] and [0166]), and the examples that have been shown (see paragraphs [0201] et seq.), Applicant believes that full scope of claims 23-25, 28-32, and 35-37 can be practiced without undue experimentation”, since claims 23-25, 28-32, and 34-37 can be directed to an in vivo method and the molecule such as a nucleic acid or an oligonucleotide has problems to be delivered to the cells having a SNCA genomic variant in vivo (see above rejection under 35 U.S.C 112 (a)), claims 23-25, 28-32, and 34-37 have an enablement issue. Furthermore, since claim 24 does not require that the SNCA-mediated gene is a specific gene, the molecule is a specific molecule, and the SNCA genomic variant is a specific SNCA genomic variant, 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, 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 such as any kind of oligonucleotide as recited in claims 24 and 25. In addition, since claim 28 does not indicate how a SNCA-medicated gene such as HERC5 gene in cells having any kind of SNCA genomic variant is correlated with phosphor-Ser473-Akt or Notch, 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 having any kind of SNCA genomic variant such as SNCA genomic variant rs356165 wherein the carrier is a Chinese subject.
Second, although applicant argues that “the Examiner also rejects claim 23 under 35 USC 102 as being anticipated using Mak (US Patent Application Publication 2015/0037257 A1), which will be addressed infra. Of note, if a prior art publication (i.e., Mak) can be used to reject independent claim 23 for novelty, Applicant submits that claim 23 must be enabled because only an enabled reference can be used to reject a claim under 35 USC 102 (see, for example, Elan Pharm., Inc. V. Mayo Found. For Med. Educ. & Research, 346 F.3d 1051 (Fed. Cir. 2003) and MPEP 2121.01. Applicant notes that if Mak is enabled, then present claim 23 must also be enabled”, nowhere in MPEP 2121.01 states that a claim is fully enable if the claim can be rejected under 35 USC 102 as argued by applicant.
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 34-37 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 in view of the phrase “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 with the molecule” because this phrase does not indicate how the cells having a SNCA genomic variant interact with the molecule. 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).
This rejection is based on that a SNCA-mediated gene in claim 23 is interpreted as a SNCA gene.
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 reasonably 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) without a molecule (ie., the herbicide paraquat (PO)) and measuring the expression of, or the activity of the gene expression product encoded by, the SNCA-mediated gene in the cells having the SNCA genomic variant with the molecule, thereby detecting a change in response to the molecule by comparing the expression of, or the activity of the gene expression product encoded by, the SNCA-mediated gene in the cells having the SNCA genomic variant with and without the 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 (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 comprises an assay that is a cell-based assay for detecting the change in the expression of, or the activity of the gene expression product encoded by the SNCA-mediated gene (ie., SNCA gene) as recited in claim 34 (see paragraphs [0090] to [0094] and Figure 2).
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).
This rejection is based on that a SNCA-mediated gene in claim 23 is interpreted as a SNCA gene.
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 reasonably 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) without a molecule (ie., a lentiviral vector comprising gRNA4-dCas9-DNMT3A expression cassette) and measuring the expression of, or the activity of the gene expression product encoded by, the SNCA-mediated gene in the cells having the SNCA genomic variant with the molecule, thereby detecting a change in response to the molecule by comparing the expression of, or the activity of the gene expression product encoded by, the SNCA-mediated gene in the cells having the SNCA genomic variant with and without the 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 (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 comprises an assay that is a cell-based assay for detecting the change in the expression of, or the activity of the gene expression product encoded by the 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.
Response to Arguments
In page 13, fourth paragraph bridging to page 14, first paragraph of applicant’s remarks, applicant argues that “[A]pplicant notes that the Examiner relies on SNCA being an SNCA-mediated gene. However, paragraph [0013] makes it clear that SNCA is an excluded gene from the group of SMCA-mediated genes. Accordingly, in construing instant claim 23 which is directed to detecting a change in expression levels of SNCA-mediated genes, the broadest reasonable interpretation of the scope of claim 23 excludes the SNCA gene as a SNCA-mediated gene. Accordingly, because instant claim 23 does not include the SNCA gene as part of the genus of SNCA- mediated genes, the anticipation rejection of claim 23 is inapposite. Because all of claims 24, 30, 32, and 34 are either directly or indirectly dependent from claim 23, their rejection using Mak is also inappropriate”.
The above arguments have been fully considered but they are not persuasive toward the withdrawal of rejection. Although paragraph [0013] of US 2022/0325346 A1, which is US publication of this instant case) shows that “[T]he present invention identified transcription factor binding sites in SNCA genomic variants and discloses unexpected effects in the transcription of genes (i.e., SNCA-mediated genes) in the chromosomal vicinity of SNCA (i.e. adjacent genes on the same chromosome or genes encoded on a separate chromosome held in close spatial proximity), excluding SNCA itself”, this paragraph does not provide a definition for “SNCA-medicated gene”. However, as shown in above rejections under 35 U.S.C. 102 (a) (1) or 102 (a) (2), since the specification defines a set of genes connected to Parkinson’s disease as “SNCA-mediated genes” (see paragraph [0002] of US 2022/0325346 A1, which is US publication of this instant case), α-synuclein (SNCA) gene can be reasonably considered as a SNCA-mediated gene. Although the claims are interpreted in light of the specification, limitations from the specification (ie., SNCA-mediated genes excluding SNCA gene itself)
are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
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.
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
July 17, 2026
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