DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/23/2026 has been entered.
Status of claim rejections
The objections of record to the specification are withdrawn in view of Applicant’s filing of a substitute specification in the response filed 02/23/2026.
The double patenting rejections of record are withdrawn in view of Applicant’s filing of the Terminal Disclaimer in the response filed 02/23/2026.
Election/Restrictions
Claims 1 and 8-9 are directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 10-12, 13, and 16-17 directed to the process of making or using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 04/29/2024 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Furthermore, the restriction requirement as set forth in the Office action mailed on 04/29/2024, has been reconsidered in view of the allowability of claims to the elected invention pursuant to MPEP § 821.04(a). The restriction requirement is hereby withdrawn as to any claim that requires all the limitations of an allowable claim. Specifically, the restriction requirement of 04/29/2024 is withdrawn. Claims 14 and 15, directed to use of the genome editing system of claim 1 and a pharmaceutical composition are no longer withdrawn from consideration because the claim(s) requires all the limitations of an allowable claim.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Objections
Claim 10 is objected to because of the following informalities: Claim 10 recites “A method of site-directed modifying a target sequence in the genome of a cell, comprising introducing the system o claim 1 into the cell.” It is suggested to Applicant to amend the claim to recite “A method of site-directed modifying a target sequence in the genome of a cell, comprising introducing the system of claim 1 into the cell.” Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 11-12 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 11 recites the limitation "wherein the cell is derived from mammals such as human, mouse, rat, monkey, dog, pig, sheep, cattle, cat; poultry such as chicken, duck, goose; plants including monocots and dicots, such as rice, corn, wheat, sorghum, barley, soybean, peanut and Arabidopsis thaliana and so on" (emphasis added). The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Furthermore, the phrase “and so on” renders the claim indefinite because it is unclear what other species of cells are also included (or excluded) from the Markush group, such that it is unclear what is or is not part of the claimed invention.
Claim 12 recites “wherein the system is introduced into the cell by a method selected from calcium phosphate transfection, protoplast fusion, electroporation, lipofection, microinjection, viral infection (e.g., baculovirus, vaccinia virus, adenovirus, adeno-associated virus, lentivirus and other viruses), gene gun method, PEG-mediated protoplast transformation, Agrobacterium-mediated transformation” (emphasis added). The use of parentheses renders the claim indefinite because it is unclear whether the species within the parentheses are part of the claimed invention. Furthermore, the use of the phrase “e.g.” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
First rejection
Claims 13 and 15-17 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
• (A) The breadth of the claims;
• (B) The nature of the invention;
• (C) The state of the prior art;
• (D) The level of one of ordinary skill;
• (E) The level of predictability in the art;
• (F) The amount of direction provided by the inventor;
• (G) The existence of working examples; and
• (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
All Wands factors listed above have been considered with regard to the instant claims, with the relevant factors discussed below:
The breadth of the claims and the nature of the invention: Instant claim 13-17 are broadly drawn to recite “A method of treating a disease in a subject in need thereof, comprising delivering to the subject an effective amount of the genome editing system of claim 1 to modify a gene related to the disease in the subject” (claim 13), “A pharmaceutical composition for treating a disease in a subject in need thereof, comprising the genome editing system of claim 1 and a pharmaceutically acceptable carrier, wherein the genome editing system is for modifying a gene related to the disease in the subject (claim 15). Dependent claim 16 recites that the subject to be treated is a mammal, and claim 17 recites the diseases are “tumors, inflammation, Parkinson's disease, cardiovascular disease, Alzheimer's disease, autism, drug addiction, age-related macular degeneration, schizophrenia, and hereditary diseases”. The claims are broad in scope, as the claims have been interpreted to broadly encompass the treatment of any and all diseases (benign tumors, any and all cancers, neurodegenerative, hereditary, inflammatory disorders, allergies, cardiovascular, soft tissue, autism, eye diseases, mental health disorders, etc.) via delivering to a subject an effective amount of the genome editing system of claim 1.
The level of one of ordinary skill: The level of ordinary skill in the art is high. This would include Ph.D. level scientists.
The state and level of predictability in the prior art: The claims broadly embrace the treatment of any and all diseases using the system of claim 1. However, it is not known or unpredictable if all diseases as encompassed by the broad scope of the instant claims can be treated using the same genome editing system.
Art recognized treatments of various disease states as encompassed by the claims:
Bourre (Genetic Abnormality Spectrum in Hematologic Cancers - Crown Bioscience. 7 March 2019; retrieved from https://blog.crownbio.com/blood-cancer-genetics-models) evidences the genetic abnormality spectrum in hematological cancers (title). Bourre evidences the various differences in genetic abnormalities across the range of hematologic malignancies, the variety of targeted agents developed, and the preclinical models to assess potential new therapeutics (pg. 2, paragraph 1). Multiple myeloma (MM) affects plasma cells within bone marrow responsible for the production of antibodies, and plasma cells accumulate in the marrow and damage or weaken the bone, inducing bone pain (pg. 2, paragraph 2). The cause of MM is is not clearly identified, but the most commonly reported genetic changes are in KRAS, NRAS, TP53, FAM46C, BRAF, DIS3, ATM, and CCND1 (pg. 2, paragraph 3). Common treatments for MM include chemotherapy, corticosteroids, immunomodulating agents, proteasome inhibitors, HDAC inhibitors, and monoclonal antibodies (pg. 2, paragraph 4).
Bourre also evidences that leukemia is caused by excessive production of abnormal white blood cells in bone marrow that circulate into the blood (pg. 2, paragraph 5). It is categorized into multiple subtypes including acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL),and chronic myeloid leukemia (CML) (pg. 2, paragraph 5). The primary genetic lesions that cause the vast majority of ALL are still unknown. The main treatment for ALL in adults is typically long-term combination chemotherapy, tyrosine kinase inhibitor targeted therapy (e.g. imatinib, dasatinib, nilotinib, ponatinib, bosutinib), blinatumomab targeting CD19, the monoclonal antibody inotuzumab ozogamicin against CD22, or the CAR-T cell therapy tisagenlecleucel targeting CD19 (pg. 3, paragraph 2-3), while CLL is treated using chemotherapy, radiation therapy, monoclonal antibodies targeting CD20, or CD52, or CD22, BTK inhibitors, PI3 inhibitors, Bcl-2 inhibitors, and autologous stem cell transplantation (pg. 3, paragraph 7), and targeted therapy for chronic myeloid leukemia uses tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, ponatinib, bosutinib) as the standard treatment, as well as chemotherapy or interferon therapies (pg. 4, paragraph 2). This reference evidences treatments associated with various forms of cancers and evidences a lack of overlapping treatment modalities, demonstrating the unpredictability in the art/lack of known treatments that are capable of treating all hematological cancers with the same compound.
Matulonis et al (Nat Rev Dis Primers. 2016 Aug 25;2:16061; hereinafter “Matulonis”) evidences that ovarian cancer can be subdivided into different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments (pg. 2, paragraph 1). Histological subtypes include epithelial cancers that account for ~90% of ovarian cancers and include serous, endometrioid, clear-cell and mucinous carcinomas (pg. 2, paragraph 1, Fig. 1, Table 1). The most commonly diagnosed ovarian cancer is high-grade serous carcinoma, and histologically and clinically, low-grade endometrioid carcinoma and low-grade serous carcinoma (LGSC) are different compared with their high-grade counterparts (pg. 2, paragraph 1). Some ovarian cancers originate from sites outside of the ovary; for example, many ovarian HGSCs probably originate in the fallopian tube, and some subsets of ovarian cancer have been shown to arise from the peritoneum (pg. 2, paragraph 2). Clear-cell and endometreoid carcinomas can originate from endometrial tissue outside the uterus (pg. 2, paragraph 2). The most active therapeutic agents against newly diagnosed ovarian cancer are platinum analogues (either cisplatin or carboplatin), with the addition of a taxane (either paclitaxel or docetaxel) (pg. 2, paragraph 4). Treatment paradigms for first-line management of newly diagnosed ovarian cancer includes surgical tumor debulking followed by combination platinum-based chemotherapy or neoadjuvant chemotherapy followed by interval surgical cytoreduction and additional chemotherapy after surgery (pg. 2, paragraph 4). This reference evidences the genetic mutations associated with ovarian cancers, as well as current treatment techniques used. It also evidences the varying molecular compositions, clinical features, and subtypes of ovarian cancers. This reference is silent to the association of similar/overlapping treatment modalities for the treatment of other cancers, demonstrating the unpredictability in the art and lack of a nexus between treatment of different diseases with the same treatment compound(s).
Flume et al. (State of progress in treating cystic fibrosis respiratory disease. BMC Med 10, 88 (2012)) teaches various treatment modalities for cystic fibrosis including CFTR gene modulation, direct instillation of salt and water in the CF airway epithelia, inhaled mannitol, and airway clearance therapies (see pg. 6-7). Flume teaches use of medications that could be used to alter properties of airway phlegm, aerosolized antibiotics, anti-inflammatory medications, and lung transplantation (see pg.6-7). Flume further teaches these therapies do not offer a cure and they mainly treat downstream complications of the pathophysiology of CF lung disease, meaning that patients continue to suffer the morbidity associated with chronic airways infection and predicted survival still lags well below what is normal (see pg. 8). Here, the art recognizes various treatment modalities for cystic fibrosis, however, even when treating the downstream complications of the disease pathophysiology, patients still carry high morbidity.
Mayo Clinic (Numerous Treatment options for Hyperthyroidism. May 6, 2012. Retrieved 09/19/2025 from https://newsnetwork.mayoclinic.org/discussion/numerous-treatment-options-for-hyperthyroidism/) teaches that “[i]n addition to surgery. . . there are three treatment options for hyperthyroidism. The first is surgery to remove the entire thyroid (thyroidectomy). Thyroidectomy is effective and carries a low risk of complications when performed by an experienced surgeon. However, it leaves a person with an underactive thyroid once the gland has been removed. . .and [they] would need to take thyroid hormone in the form of a pill, once daily for the rest of [their] life to regulate [the] body’s metabolism. . .The second option is radioactive iodine therapy. A radioactive form of iodine is givenby mouth and becomes concentrated in the thyroid. The radiation destroys the thyroid gland tissue over several weeks. . . The third option is to take an oral anti-thyroid medication, typically propylthiouracil ormethimazole (Tapazole), which prevents the thyroid from producing too muchhormone. Symptoms usually begin to improve in six to 12 weeks, but medicationtherapy typically continues for at least a year or more” (see pg. 2-3). Here, the art only recognizes 3 different treatment modalities for hyperthyroidism.
Yang et al (Current Pharmaceutical Design, 2014, 20, 5186-5193; hereinafter “Yang”) teaches glutamate-mediated signaling and autism spectrum disorders: emerging treatment targets (title). Yang teaches that glutamate, the major excitatory neurotransmitter in the human central nervous system, is hypothesized to play important roles in the pathophysiology of ASD and molecules involved in glutamate-mediated signaling may provide potential targets for novel, targeted drug treatment (pg. 5186, col 1, paragraph 2). Glutamate receptors are highly complex and fall into two main categories, ionotropic (voltage sensitive) and metabotropic (ligand sensitive), and Each ionotropic or metabotropic receptor has three types, depending on binding specificity, ion permeability, conductance properties and other factors (pg. 5186, col 2, paragraph 2). Ionotropic AMPA receptors are the principal transducers of the fast excitatory neurotransmission that regulates the strength of glutamatergic excitatory synapses and NMDA receptors mediate a slower component of excitatory transmission and are critical postsynaptic mediators of activity-dependent synaptic plasticity (pg. 5186, col 2, paragraph 2). Genetic studies using single nucleotide polymorphisms surrounding the NMDA receptor, kainate receptor and cell adhesion molecule cadherin 9/10 genes, have implicated them as risk factors for ASD (pg. 5186, col 2, paragraph 2). The second category of glutamate receptors is called metabotropic glutamate receptors (mGluRs), a family of receptors classified into three groups based on their sequence homology, agonist and antagonist pharmacology, and coupling to signal transduction pathways (pg. 5186, col 2, paragraph 2; pg. 5187, FIG 1).
Yang also teaches the importance of determining the signaling pathways in which disease-risk genes function as a means to identify new candidate genes and new pharmacological therapeutic targets by identifying more approachable proteins (pg. 5190, col 1, paragraph 2). Yang further teaches that there is little known about “non-syndromic” or idiopathic ASD pathophysiology, that is, ASD not in conjunction with congenital malformations and/or dysmorphic features (pg. 5190, col 1, paragraph 3) and that it is difficult to translate confidently the findings from animal models of monogenetic disorders comorbid with ASD to humans with an entire spectrum of ASD (pg. 5190, col 1, paragraph 3). Demonstrating a connection between genes involved in synaptic functions and structures in patients with ASD is insufficient to develop drug candidates, because the precise mechanisms of disease causation is not yet understood (pg. 5190, col 1, paragraph 3). This reference evidences that there is a lack of connection regarding the genes involved in changed synaptic function in patients with ASD associated with mutations and the structures in patients with ASD, which is insufficient to develop drug candidates because the precise mechanisms of disease causation is not yet understood.
The art above shows various treatment of different diseases, but all the references are silent to the ability to treat all the above disease states with the same treatment. Different types of diseases have different etiologies, even diseases within the same broad category (e.g., hereditary disorders like cystic fibrosis and sickle cell anaemia), and thus cannot all be treated the same way. Simply put, there is no single, end-all-be-all treatment capable of treating the broad genus of any and all disorders encompassed by the instant claims. The art available at the time of filing fails to exemplify the efficacy of a single product against all disorders generally.
Thus, the state of the art suggests the unpredictability of the treatment of any and all diseases as encompassed by the broad scope of the instant claims.
The amount of direction provided by the inventor and the existence of working examples: The instant specification only discloses examples involving the creation and screening of C2C1 proteins before using the chimeric sgRNA scaffold for the transfection of human 293T embryonic kidney cells (see Examples 1-4) as well as the sequences identified by Applicant (see Table 1-2).
There is no evidence, direction, or working examples from the specification the treatment of any and all diseases, apart from the speculative embodiments through the disclosure, as broadly encompassed by the claimed invention. It is therefore unknown if the genome editing system as disclosed in the specification, would reliably be considered a treatment method for all disorders as broadly encompassed by the claimed invention. As such, there is a lack of reasonable direction in the specification to support the scope encompassed by the claims for the treatment of any hematological or ovarian cancer based on the identified screened compound(s).
Quantity of experimentation needed to make or use the invention based on the content of the disclosure: Given the state of the art regarding various related and unrelated disease states, and treatments associated with those disorders, the lack of a connection between overlapping or a single treatment modality capable of treating them, and Applicant’s lack of working examples, one of ordinary skill would not have been able to practice the instantly claimed invention without undue experimentation. For example, it is highly unknown or unpredictable if the genome editing system with C2C1 proteins would be capable of effectively treating Hodgkin lymphoma, high-grade serous ovarian carcinoma, bipolar disorder, methamphetamine addiction, cystic fibrosis, chronic urticaria, hyperthyroidism, sickle cell anemia, Parkinson’s and Type 2 diabetes. Nothing in the specification remotely demonstrates or suggests that the claimed compositions would have any efficacy against all of these exemplified disease states, because the specification does not have any data suggesting that the compositions were ever administered to a subject or subjects encompassed by the instant claims.
Though not controlling, the lack of working examples is, nevertheless, a factor to be considered in a case involving both physiological activity and an underdeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, they run the risk that unless one of ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilosky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
The essential elements toward validation of a therapeutic is the ability to test the drug on subjects monitored during clinical symptoms of various disorders (e.g., autism, hyperthyroidism, depression, Alzheimer’s, sickle cell, wet AMD, high blood pressure, etc.), and link those results with subsequent histological confirmation of the presence, decrease, or absence of symptomology. This irrefutable link between antecedent drug and subsequent knowledge of treatment of the reaction is the essence of a valid treatment agent. All of this underscores the criticality of providing workable examples which are not disclosed in the specification for any and all disorders as instantly claimed.
In essence, the specification merely presents an idea of, and leaves it entirely up to the practitioner to determine how to carry out the claimed methods. It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor or exemplified in the specification, reasonable detail must be provided in order to enable one of ordinary skill to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph.
Therefore, 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 the claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 14 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because “use” claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101. In re Moreton, 288 F.2d 708, 129 USPQ227, 228 (CCPA 1961) (“one cannot claim a new use per se, because it is not among the categories of patentable inventions specified in 35 U.S.C. 101”). In this case, claim 14 is drawn to “”. However, said claim fails to recite at least one of the four categories of patent eligible subject matter.
Therefore, the claim does not qualify as eligible subject matter under 35 USC 101.
Allowable Subject Matter
Claims 1, 8, and 9 allowed.
The following is a statement of reasons for the indication of allowable subject matter: the claimed invention is drawn to “A genome editing system for site-directed modification of a target sequence in the genome of a cell, comprising at least one of the following i) to v):i) a C2cl protein and a guide RNA; ii) an expression construct comprising a nucleotide sequence encoding a C2cl protein and a guide RNA; iii) a C2c1 protein and an expression construct comprising a nucleotide sequence encoding a guide RNA; iv) an expression construct comprising a nucleotide sequence encoding a C2c1 protein and an expression construct comprising a nucleotide sequence encoding a guide RNA; v) an expression construct comprising a nucleotide sequence encoding a C2c1 protein and a nucleotide sequence encoding a guide RNA; wherein: (a) the guide RNA is capable of forming complex with the C2c1 protein and targeting the C2c1 protein to the target sequence in the cell genome; (b) the C2c1 protein comprises the amino acid sequence set forth in any one of SEQ ID NOs: 1-10; and (c) the guide RNA is an sgRNA comprising an sgRNA scaffold sequence encoded by a nucleotide sequence selected from SEQ ID NOs: 39-75.” As noted in the Final Office Action, after search of Applicant’s elected species of sgRNA (SEQ ID NO: 51), the sequence has been deemed novel and unobvious over the prior art. The examiner opened the search to include the other species (SEQ ID NO: 39-50 and 52-75), and has deemed them to also be novel and unobvious over the prior art. As the claimed sequences are novel and unobvious, the claimed genome editing system is also deemed novel and unobvious over the prior art. The closest prior art was made of record (see the previously cited Inouye reference).
Conclusion
CLAIMS 1, 8, 9 ALLOWED.
CLAIMS 10-17 ARE REJECTED.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGIANA C REGLAS whose telephone number is (571)270-0995. The examiner can normally be reached M-Th: 8:00am-2:00pm.
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672