DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
This action is written in response to applicant’s correspondence received on 12/14/2023. Claims 1-9 are currently pending.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged based on an application filed in United Kingdom 2108867.9 on 06/21/2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings are objected to because:
1). 37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."” In the current case, the view numbers for FIGs. 1-11 are preceded by the word "FIGURE" instead of the abbreviation "FIG.".
2). 37 CFR 1.84(p)(1) states “Reference characters (numerals are preferred), sheet numbers, and view numbers must be plain and legible, and must not be used in association with brackets or inverted commas, or enclosed within outlines, e.g., encircled. They must be oriented in the same direction as the view so as to avoid having to rotate the sheet.”
In the current case, FIGs. 1-5, 7-8 show sheet numbers and view numbers in upright orientation while the drawings require rotation.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 61. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term Promega, OptiMEM, Puregene, Thermo Fisher Scientific, Invitrogen, GenBank, Cellecta, which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 7 is objected to because of the following informalities: Step C1) should end with a “,” instead of “.”. Each claim is required to begin with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See MPEP §608.01(m).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-6, 8, 9 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.
Regarding claim 1,
1) The preamble recites “and/or for accessory molecules needed for …”. It is unclear whether the clause is meant to be a substantive alternative limitation, in which case the claim is indefinite and incomplete as to how that alternative is practiced because no step is recited in the body of the claim regarding this alternative, or merely intended use that doesn’t limit the scope of the claim.
2) The recitation "said functional expression" in the preamble creates indefiniteness. There is insufficient antecedent basis for this limitation in the claim, because the preamble recites “a cell expressing a functional olfactory receptor”.
3) Step A recites 2 separate instances of “an olfactory receptor”, it is not clear how these two instances of “an olfactory receptor” relate to each other or whether they refer to the same receptor or to different olfactory receptors because there are distinctions between these recitations: the first one directs to a functional limitation of a nucleic acid construct inducible by an olfactory receptor with high degree of generality, i.e. any olfactory receptor and not required to be present in a cell, whereas the second recitation refers to a specific olfactory receptor encoded in a second nucleic acid construct for expression in a cell, i.e. a required limitation of the subject of selection.
5) Step B recites “said olfactory receptor”, it is not clear which “an olfactory receptor” it refers to regarding the preceding instances of recitation in step A because item 3) above creates ambiguity.
6) Step C1 recites “the olfactory receptor”, it is not clear which “an olfactory receptor” it refers to in the preceding step A because item 3) above creates ambiguity.
Regarding claim 2, the same recitations 1)-6) above are also considered indefinite herein.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim 1 or 2 but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 7 are rejected under 35 U.S.C. 103 as being unpatentable over Kosuri (WO2019010270A1, published on 01/10/2019; Cited on IDS filed on 12/14/2023), in view of Chua (WO9938988.Published on 08/05/1999).
Kosuri (2019) teaches a method of selecting for cells expressing a functional olfactory receptor (OR) in a cell using a multiplexed odorant-receptor interaction screening system (Pages 130-132, Example I; Pages 167, claim 92; Pages 168-169, claim 107), comprising:
Providing HEK293T cells (Page 131, ¶[0228], line 13). The cells express a genetic reporter for cAMP signaling (Page 131, ¶[0228], line 12) encoded by a nucleic acid construct driven by an inducible promoter (Page 160, claim 5), wherein the receptor-responsive element comprises one or more of a cAMP response element (CRE), a nuclear factor of activated T-cells response element (NF-AT-RE), etc. (Page 161, claim 17). The cells express one olfactory receptor from a plasmid library, i.e. a second nucleic acid construct (Page 131, ¶[0228], lines 17-18). Upon odorant, i.e. ligand, binding, the transcription of a downstream reporter gene is turned on (Page 131, ¶[0228], lines 13-17), the reporter gene can be an antibiotic resistance gene (Page 109, ¶[0151], lines 25-26).
Kosuri teaches contacting cells with ligand as a step (Page 167-168, claims 92 & 107).
C1) Kosuri teaches the option to use antibiotic resistance gene that confers resistance to the toxic effect of an antibiotic in the inducible reporter nucleic acid construct (Page 109, ¶[0151], lines 25-26).
Kosuri does not explicitly teach selecting cells expressing functional olfactory receptors by culturing cells with the antibiotic and the ligand together.
However, Chua (1999) teaches a method of selecting cells by culturing them in the presence of an antibiotic and a ligand, based on the ligand binding to functional receptors expressed on the surface of the cells and the ligand-induced activation of expression of an antibiotic resistance gene (Page 4, lines 6-9, 26-27; Page 21, Example 14; Page 22, lines 1-4).
Regarding claim 1, it would have been obvious to persons having ordinary skills in the art (PHOSITAs) before the effective filing date of the claimed invention to have further modified the cell selection method taught by Kosuri (2019) by incorporating the teachings of Chua (1999) by maintaining the presence of the ligand used to bind the olfactory receptor expressed by the cells under selection while providing the antibiotic, thereby “culturing them in the presence of the antibiotic and the ligand”. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results in selecting for cells expressing a functional olfactory receptor that binds to the ligand. One would have been motivated to do so because Kosuri (2019)’s teaching regarding the option of using antibiotic resistance gene as a reporter gene in the nucleic acid construct lacks operational detail, but Chua (1999) fills the gap of experimental design details necessary to carry out the method with success. One would have reasonable expectation of success because the selection method taught by Chua supplements Kosuri’s general teaching of using this strategy to select active olfactory receptor binding with ligand. The teachings from Kosuri and Chua are congruent and point to the same predicted outcome, i.e. successful selection of cells with expression of functional receptors that activate inducible antibiotic resistance gene expression by ligand binding.
Regarding claim 7, Kosuri further teaches:
Providing a heterogeneous population of cells, wherein said cells comprise: 1) an inducible reporter comprising a receptor-responsive element, such as CRE (Page 161, claim 17); wherein expression of the reporter is dependent on the activation of the activity of the receptor encoded by the receptor gene (Page 163, claim 45), wherein the reporter gene can be an antibiotic resistance gene (Page 109, ¶[0151], line 25); 2); wherein each cell expresses a different receptor (Page 163, claim 45).
(D) Kosuri further teaches a method of determining the identity of the one or more reporters; wherein the identity of the reporter indicates the identity of the bound receptor (Page 167-168, claims 92-99), which is an embodiment of determining the nucleotide sequence encoding the receptor in the selected cells under broadest reasonable interpretation.
Claims 8 & 9 are rejected under 35 U.S.C. 103 as being unpatentable over Kosuri (2019; Cited on IDS filed on 12/14/2023), in view of Chua (1999), as applied to claim 1 above, and further in view of Guo (J Biol Chem. 297(1):100838; Epub 2021 May). The rejection of claim 9 is evidenced by Fuerer (PLoS One. 2010 Feb 23;5(2):e9370).
The teachings of Kosuri (2019) and Chua (1999) have been discussed above as applied to claims 1 and 7. Neither Kosuri nor Chua teaches a “sub-culturing step” or “enriched in culture”, or “puromycin-N-acetyltransferase”.
However, Guo (2021) teaches that “The drug-resistant cells … were then pooled … and expanded until they had grown for 4 weeks from the date of transfection in selective media” (Page 9, right column, 2nd ¶, lines 12-15). This is equivalent to “sub-culturing step” or “enriched in culture”. Guo further teaches “…, PuroR, … , which confer resistance to the selective antibiotics …, puromycin, …” (Page 1, last ¶, lines 5-8). PuroR is puromycin-N-acetyltransferase, as evidenced by Fuerer (2010; Page e9370, Abstract, line 7: PuroR (puromycin Nacetyltransferase)).
Regarding claim 8, it would have been obvious to persons having ordinary skills in the art (PHOSITAs) before the effective filing date of the claimed invention to have further modified the cell selection method taught by Kosuri (2019) by incorporating the teachings of Chua (1999) and Guo (2021) by selecting for cells expression a functional olfactory receptor by “culturing them in the presence of the antibiotic and the ligand”, followed by a “sub-culturing step” to enrich the selected cells. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results in selecting for cells expressing a functional olfactory receptor that binds to the provided ligand. One would have been motivated to do so because Kosuri (2019)’s teaching regarding the option of using antibiotic resistance gene as a reporter gene in the nucleic acid construct lacks operational detail, but Chua (1999) and Guo (2021) fills the gap of experimental design details necessary to carry out the method with success. One would have reasonable expectation of success because the selection method taught by Chua and Guo supplements Kosuri’s general teaching of using this strategy to select active olfactory receptor binding with ligand. The teachings from Kosuri, Chua, and Guo are congruent and point to the same predicted outcome, i.e. successful selection of cells with expression of functional receptors that activate inducible antibiotic resistance gene expression by ligand binding.
Regarding claim 9, Guo (2021) further teaches “puromycin-N-acetyltransferase”.
Claims 2 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Kosuri (2019), in view of Chua (1999), further in view of Ikegami (Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):2957-2967), Pelham (EMBO J. 1988 Jun;7(6):1757-62), Glazer (Proc Natl Acad Sci U S A. 1986 Feb;83(4):1041-4), and Timms (Nat Commun. 2016 Jun 10;7:11786).
The teachings of Kosuri (2019) and Chua (1999) have been discussed above as applied to claim 1, 7-9. Neither Kosuri nor Chua teaches applying mutagenesis to the cells in step (A).
However, Ikegami (2020) teaches that “Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies” (Page 2957, left column, lines 3-5). This addresses a known problem for functional olfactory receptor expression. Ikegami does not teach applying mutagenesis to cells expressing olfactory receptors.
However, Pelham (1988) teaches a mutagenesis-and-selection screen used specifically to identify genes governing ER retention. Based on the knowledge that luminal endoplasmic reticulum (ER) proteins are prevented from being secreted by a sorting system, which is identified using mutants with defective sorting systems under genome-wide mutagenesis using UV irradiation of yeast cells (Page 1762, left column, 2nd ¶). Pelham also teaches that the sorting system is highly conserved across yeast cells and vertebrate animal cells, which have homologous sorting system (Page 1757, Abstract, lines 3-5), hence the strategy of using genome-wide mutagenesis to study regulators of ER retention can be applied to investigate trafficking and ER retention in mammalian cells using an equivalent genome-wide mutagenesis strategy. In addition, Glazer (1986) teaches that “the primary site of UV mutagenesis in mammalian cells is at pyrimidine-cytosine (Y-C) sequences, and that the most frequent mutation at this site is a C-T transition” (Page 1041, Abstract, last line), indicating the Pelham’s UV irradiation-based mutagenesis should not be directly applied to mammalian cells due to the bias in mutation loci. Neither Pelham nor Glazer teaches a genome-wide mutagenesis strategy suitable for vertebrate animal cells.
However, Timms (2016) teaches genome-wide CRISPR/Cas9-mediated mutagenesis-based forward genetic screens to identify genes required for the endoplasmic reticulum-associated degradation (ERAD; Page 1, Abstract, lines 5-8; Page 3, Figure 1).
Regarding claim 2, it would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have further modified the cell selection method taught by Kosuri (2019) to comprise a mutagenesis step to the cells taught by Timms (2016). It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results in identifying potential regulators that contribute to the observed challenges, namely ER retention, in functional expression of difficult-to-study olfactory receptors. One would have been motivated to do so because Ikegami (2020) teaches that there is a causal relationship between ER retention and lack of functional olfactory receptors expression. One would have reasonable expectation of success because the mutagenesis screen method taught by Pelham (1988) and Timms’s genome wide CRISPR/cas mutagenesis function in the same way in highly homologous systems despite a necessary adjustment in technique based on the observation of Glazer to apply an equivalent mutagenesis method in yeast cells to vertebrate animal cells such as HEK293T cells used by Kosuri (Page 131, ¶[0228], line 13; Page 154, ¶[0249], line 1; Claim 90).
Regarding claim 6, Timms (2016) teaches genome-wide CRISPR/Cas9-mediated mutagenesis (Page 1, Abstract, lines 5-8; Page 3, Figure 1).
Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Kosuri (2019), in view of Chua (1999), Ikegami (2020), Pelham (1988), Glazer (1986), and Timms (2016), further in view of Kandel (Proc Natl Acad Sci U S A. 2005 May 3;102(18):6425-30).
The teachings of Kosuri (2019), Chua (1999), Ikegami (2020), Pelham (1988), Glazer (1986), and Timms (2016) have been discussed above as applied to claim 1, 2 & 6-9.
None of Kosuri, Chua, Ikegami, Pelham, Glazer, and Timms teaches applying insertional mutagenesis to the cells in step (A).
However, Kandel (2005) teaches that “insertional mutagenesis with retroviral vectors and show that the ability to induce mutations increases greatly if a randomly inserted promoter directs transcription into the host DNA” (Page 6425, Abstract, lines 6-9).
Regarding claim 3, it would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have further modified the cell selection method taught by Kosuri (2019) to comprise a mutagenesis step to the cells taught by Kandel (2005). One would have been motivated to do so because Ikegami (2020) teaches that there is a causal relationship between ER retention and lack of functional olfactory receptors expression. One would have reasonable expectation of success because of the effectiveness of the forward genetic mutagenesis screen method taught by Pelham (1988) in identifying potential engineering targets in yeast, which has a highly homologous ER sorting system with that of mammalian cells, and Timms’s genome wide CRISPR/cas mutagenesis approach works in the same way in identifying a regulator gene of endoplasmic reticulum-associated degradation (ERAD) in human cells, since there is a known obstacle in directly applying the UV-based mutagenesis method to mammalian cells based by discoveries of Glazer. One would be further motivated to substitute Timm’s method with Kandel’s reversible insertional mutagenesis method because of the additional benefits of “simplicity and robust target validation” (Page 6425, Abstract, lines 17-18). It would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results in identifying potential regulators for functional expression of difficult-to-study olfactory receptors, because the methods are similar approaches with genome wide reach. The CRISPR/cas methods do provide the benefit of rational targeting using guide RNA designs, hence both methods have different benefits and would have been obvious to be run in parallel.
Regarding claim 4, Kandel further teaches random insertion of promoter sequence and demonstrates activation of endogenous genes, such as RelA (Page 6428, right column, 2nd ¶, lines 19-22; Figure 4C), hence, suitable for activation of endogenous genes.
Regarding claim 5, Kandel teaches using PCR and genome sequencing to map and identify the insert site of the inserted nucleic acid sequence (Page 6428, right column, 2nd ¶, last 4 lines).
Subject Matter Eligibility Analysis
Regarding claim 5, it is noted that the claim is a method claim that inherits all limitations of claim 3, from which it depends from, and inherits all limitations of claim 2, from which claim 3 depends from. Claims 2 and 3 direct to a process (Step 1: Yes). Claim 5 further recites a step involving mental process, which is a judicial exception (JE) because of the recitation “the insertion site … is mapped and/or identified”, which involves abstract idea in correlation and mental comparison of aligned sequences (Step 2A prong 1: Yes). Furthermore, the claim does not recite additional elements that integrate the JE into a practical application (Step 2A prong 2: No). However, the claim inherits step C1) from claim 2 it indirectly depends from via claim 3, and step C1) amounts to significantly more because it is not routine in the art to combine treating cells with an antibiotic and treating cells with a ligand for selecting cells expressing functional olfactory receptor (Step 2B: Yes), as evidenced by the lack of anticipatory prior art.
Hence, claim 5 is eligible.
Regarding claim 7, the same rationale laid out above applies to the analysis. Step C1) amounts to significantly more because it is not routine in the art to combine treating cells with an antibiotic and treating cells with a ligand for selecting cells expressing functional olfactory receptor (Step 2B: Yes).
Hence, claim 7 is also eligible.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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