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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 05/22/2026 is acknowledged. Claims 20-22,29 and 30 were cancelled. Claims 16,18,19,23,24,26,28,31 and 32 were amended.
Applicant elected an oligonucleotide as the inhibitor, specifically an shRNA as the oligonucleotide in claims 22 and 30, more specifically SEQ ID NO: 1 as the shRNA in claims 23,24,31 and 32 without traverse in the reply filed on 11/17/2025 is acknowledged. The Examiner expanded the species election to the oligonucleotide of SEQ ID NO: 2. However, the claims have been amended and no longer recite SEQ ID NO:1 or 2.
Claims 16-19,23-28 and 31-34 are under examination.
Priority
This application is a 371 of PCT/EP2021/054190, filed 02/19/2021, and claims foreign priority to EP20158875.3, filed 02/21/2020.
Withdrawn Objections and Rejections
Applicant’s arguments and amendments, see page 8, filed 05/22/2026, with respect to the objections to claims 16-34 for using the acronym EXT1, and claims 23,24,31,32 for bolded SEQ ID NOs have been fully considered and are persuasive due to the amendments to the claims correcting the above issues. However claim 26 remains objected to (see below).
Applicant’s arguments and amendments, see pages 8-9, filed 05/22/2026, with respect to the Improper Markush Grouping rejection of claims 21 and 29 have been fully considered and are persuasive due to the cancelation of these claims and the amendments to the claims limiting to certain shRNA. The Improper Markush rejection of claims 21 and 29 has been withdrawn.
Applicant’s arguments and amendments, see page 9, filed 05/22/2026, with respect to the 35 U.S.C. 112(b) rejection of claims 16-25 and 28-30 have been fully considered and are persuasive due to the amendments to the claims removing indefinite language “preferably” and amendments to the claims to recite proper Markush grouping language. The 35 U.S.C. 112(b) rejection of claims 16-25 and 28-30 has been withdrawn.
Applicant’s arguments and amendments, see page 10, filed 05/22/2026, with respect to the 35 U.S.C 102(a)(1) rejection of claims 16-22 and 25 as anticipated by EP 3604502 (Tokyo), the 103 rejection of claims 22-24 as unpatentable over Tokyo and further in view of CN 107058476 (Chen), the 103 rejection of claims 26-30,33,34 as unpatentable over Tokyo and the 103 rejection of claims 30-32 as unpatentable over Tokyo and further in view of Chen, have been fully considered and are persuasive due to the amendments to the claims limiting the shRNA to Table 5 and variants thereof and which art was not applied to. Therefore the rejections have been withdrawn. However, upon further consideration, new grounds of rejection are made in view of the amendments limiting the sequence of the oligonucleotide inhibitor to SEQ ID NOs: 35,36,39,43,44,48,50 and 52 which were not previously examined. See the 103 rejection below, which still uses Tokyo as a base reference, and uses a new reference to teach the limitations of the shRNA sequence. Regarding Applicant’s arguments on page 11 that the difference between amended claim 16 and Tokyo is that amended claim 16 uses a specific selection of shRNA sequences which induce reduction of EXT1 level in cells (Table 5, Fig. 33) and a person of ordinary skill in the art would not have found in Tokyo any teaching that would have led one towards the claimed sequences, Tokyo teaches producing a virus in cells which preferably do not express EXT1 and that EXT1 can be deleted by a method known in the art, such as knockout by gene editing using CRISPR/Cas9 or suppressed (knockdown) by gene silencing using siRNA or the like, and cites the GenBank Accession No. NM_000127 for human EXT1 gene (paragraph 0036). Tokyo does not limit EXT1 knockout to just using gRNA but also teaches that gene silencing using siRNA or the like may be used. Therefore, Tokyo provides the suggestion that other methods of gene silencing may be used.
Claim Objections
Claims 16,23,24,26,31 and 32 are objected to because of the following informalities: In each of the above claims, the word “of” is missing between “sequences” and “SEQ ID NO: 35, SEQ ID NO: 36…..and SEQ ID NO: 52”. Appropriate correction is required.
Claims 16,23 and 24 are objected to because of the following informalities: Each of the above claims recites “wherein said inhibitor of the EXT1 expression or activity is selected in a group consisting of…”. The Examiner suggests amending the claims to recite “selected from the group consisting of” which is more consistent with proper Markush language. Appropriate correction is required.
Claim 26 is objected to because of the following informalities: step b) in claim 26 has a coma after “entity” rather than a semicolon. Step c) was amended to remove the comma and now has no punctuation between step c) and the added wherein statement. The examiner suggests placement of a semicolon after step c). Appropriate correction is required.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. See at least pages 43 and 54-56 of the substituted specification filed 05/22/2026 which still recites multiple instances of “www.”.
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.
Written Description Rejection
Claims 16-19,23,25-28,31,33 and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 16-19,23-28,31,33 and 34 are directed to encompass a method for production of a biological entity (polypeptide or viral particle) in a cell comprising a step of providing a cell population having at least depleted EXT1 expression and/or activity obtained by treatment of said cell with an inhibitor of EXT1 expression and/or activity, wherein said inhibitor of the EXT1 expression and/or activity is selected in a group consisting of a genus of oligonucleotide having at least 75% identity with any one of sequences SEQ ID NO: 35,36,39,43,44,48,50 and 52. Claims 23 and 31 require the oligonucleotide to have at least 90% identity with any one of SEQ ID NO: 35,36,39,43,44,48,50 and 52. Therefore, these claims encompass the recited method using variants of the recited sequences. Claims 24 and 32 are interpreted as requiring the entire sequence of the recited sequences and therefore are not included in the written description rejection. Therefore, the instant claims recite a method of producing a biological entity (a polypeptide or viral particle) comprising a step of providing a cell population produced by depleting EXT1 expression and/or activity using a genus of oligonucleotide EXT1 inhibitors having at least 75% or at least 90% identity to SEQ ID NO: 35,36,39,43,44,48,50 and 52, which only correspond in some undefined way to specifically instantly disclosed shRNAs.
Regarding the state of the art, Tokyo (EP3604502, Published 5 Feb 2020), cited on an IDS, teaches methods for stably propagating virulent hand, foot and mouth disease viruses (paragraph 0007) and host cells therefore that preferably do not express the EXT1 gene (paragraphs 0011,0035), and preparing RD cells expressing no heparan sulfate by genome editing using CRISPR/Cas9. Tokyo teaches the sequence of the guide RNA targeting the EXT1 gene was designed and shown below (paragraph 0072).
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Scadden et al. taught the discovery that small hairpin RNAs or short hairpin RNAs (shRNA) that target six proteins, when transduced into an isolated cell population of primary HSPCs, increased the colony forming capacity and the long-term culture forming capacity of the HSPCs. The transduced isolated cell population of primary HSPCs scored two- to five-fold higher in a standard methylcellulose colony forming cell assay (CFC) and over 100 fold higher in a standard long term culture initiating cell assay (LTC-IC). One of the six target proteins is exostoses 1 (EXT1) (paragraph 0006). Scadden et al. taught the RNAi agent is a shRNA that comprises a sequence selected from the group consisting of SEQ ID NOS: 2, 5, 8, 16, 17, and 18 (paragraph 0028, 0032) and in one embodiment, the RNAi agent inhibits gene expression of EXT1 and the RNAi agent comprises SEQ ID NO: 5 (paragraph 0104). The EXT1 shRNA of SEQ ID NO: 5 of Scadden et al. is 100% identical to instant SEQ ID NO: 35.
Therefore, the state of the art teach virus production in cells by gene editing using sgRNA targeting EXT1 and suggests gene silencing using siRNA or the like, and teaches shRNA sequences that interfere with EXT1 expression in cells.
The instant examples disclose EXT1 shRNAs of SEQ ID NOs: 1-24 on pages 31-33 and SEQ ID NOs: 33-53 on pages 56-57 and EXT1 siRNAs of SEQ ID NOs: 25-28 on page 34. The results on page 55 for Example 2 show HEK293 shEXT1 produce approximately four times more lentiviral particles than the HEK293 shCTRL cells (Fig. 28) and approximately three times more AAV2 viral particles than HEK293 shCTRL cells (Fig. 29), as well as expressing 2.9 times more Notch1-Flag protein than control cells (Fig. 30) and 1.7 times more nano-luciferase enzyme than control cells (Fig. 31).
However, it cannot be determined what the shRNA sequences were that had the function of depleting EXT1 expression and/or activity and production of the polypeptide or viral particle in the cell the cell population in order to determine the required structure that performs the recited functions. Example 4 on page 58 shows testing EXT1 targeting shRNA shown in Table 4, including #1 and #20 in HEK293 cells lines, which are then infected with lentiviral or AAV2 particles expressing Nano-luciferase enzyme or green fluorescent protein. Results of the western blot shows that not all shRNA sequences used are able to reduce the levels of EXT1 expression in HEK293 cells, and 8 out of 20 tested shRNAs were identified as able to induce reduction of EXT1 levels in cells, which are shRNA#3,4,7,11,12,16,18 and 20 which are SEQ ID NOs: 35,36,39,43,44, 48,50 and 52 respectively (Table 5, page 59). EXT1 knockdown confirmed cells were transduced with nanoluciferase expressing lentivirus or GRP expression AAV2 virus, and results were that shRNA #3 and #7 exhibited the highest productivity in both lentiviral and AAV systems (Page 59 and Fig. 33A-B) and other EXT1 knockdown cells lines showed significant productivity compared to control cells with shEXT1 #12,16 and 20 for lentiviruses (Fig. 33A) and shEXT1 #11,12,16 and 20 for AAV viruses (Fig. 33B).
Therefore, the specification discloses that not all shRNA EXT1 sequences reduce EXT1 expression in cells, and those that did reduce EXT1 levels were SEQ ID NOs: 35,36,39,43,44, 48,50 and 52 respectively (Table 5, page 59), which is the entire sequence of the above SEQ ID NOs and not 75% or 90% identity to those sequences. While claims 16-19,23,25-28,31,33 and 34 recite the EXT1 inhibitor has at least 75% or at least 90% identity with any one of SEQ ID NOs: 35,36,39,43,44,48,50 and 52 the specification shows the recited function for the entire sequences of SEQ ID NOs: 35,36,39,43,44,48,50 and 52, and not 75% or 90% of one of those sequences.
An ordinary artisan would not know what the required structure is to perform the function as there is no common or core structure shared by the species to know what portions are required to achieve the recited function. One would not know what portions of the sequences at 75% or 90% identity would be required to perform the recited functions.
Therefore, the instant specification discloses how to produce a polypeptide or viral particle in a eukaryotic cell that has been depleted of EXT1 expression and/or activity using the entire sequence (or 100% identity) of the shRNAs described in Table 5, page 59. Other than the complete sequence of these EXT1 shRNAs in Table 5 on page 59, none of these EXT1 inhibitors meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, due to lacking chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further
supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above specifically disclosed shRNAs in Table 5 (100% identity), the specific EXT1 guide RNA of Tokyo, and the EXT1 shRNA sequence of Scadden et al., the skilled artisan cannot envision the detailed chemical structure of the oligonucleotide inhibitors with at least 75% or at least 90% identity to the recited sequences with the recited function of depleting EXT1 expression and/or activity and resulting in production of a polypeptide or viral particle. The sequences of SEQ ID NOs: 35,36,39,43,44,48,50 and 52 are completely different and do not appear to share a common or core structure, and no structure-function correlation has been provided regarding what the required core structure of the oligonucleotide that has the recited function of depleting EXT1 expression and/or activity in a cell population and the function of producing a polypeptide or viral particle in a cell population. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003).
Therefore, only the above chemically structurally defined EXT1 shRNAs in Table 5 at 100% identity, the specific EXT1 guide RNA of Tokyo, and the EXT1 shRNA sequence of SEQ ID NO: 5 of Scadden et al., but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
Response to Arguments
Applicant's arguments and amendments, filed 05/22/2026 have been fully considered but they are not fully persuasive.
Applicant argues on page 10 that claims 16 and 26 were amended to the shRNAs of Table 5 and variants thereof, and sequences in claims 23,24,31 and 32 were amended accordingly and therefore the subject matter of instant claims 16-34 is sufficiently described in the application as filed.
This is not found completely persuasive. While Applicant’s amendments do help with the Written Description rejection as the genus of inhibitors was further limited and narrowed, the amended claims still encompass variants of the recited sequences as Applicant stated. The sequences that the Examiner stated had written support for are specifically recited in the claims, however claims 16-19,23-28,31,33 and 34 still recite variants of these sequences as the oligonucleotide may only have 75% identity or 90% identity to the recited sequences, and the specification has not provided written support for the variants of these sequences. An ordinary artisan would not know what the required structure is to perform the function as there is no common or core structure shared by the species to know what portions are required to achieve the recited function. One would not know what portions of the sequences at 75% or 90% identity would be required to perform the recited functions. Therefore, the Examiner has maintained the Written Description rejection for claims 16-19,23-28,31,33 and 34.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 16-19,23-28 and 31-34 are rejected under 35 U.S.C. 103 as being unpatentable over Tokyo (EP3604502, Published 5 Feb 2020), cited previously, in view of Scadden et al. (US 20110305675, Published 15 Dec 2011), both cited on an IDS.
Regarding claims 16,18,19,23,24,26,28,31 and 32, Tokyo teaches methods for stably propagating virulent hand, foot and mouth disease viruses (paragraph 0007) and host cells therefore that preferably do not express the EXT1 gene (paragraphs 0011,0035). Tokyo teaches EXT1 as a gene encoding an enzyme involved in the biosynthesis of heparan sulfate and that biosynthesis of heparin sulfate is inactivated due to a gene encoding the enzyme not being expressed (paragraph 0035) and the expression of the gene involved in biosynthesis of heparan sulfate can be deleted by a method known in the art, such as knockout by gene editing using CRISPR/Cas9 or suppressed (knockdown) by gene silencing using siRNA or the like, and cites the GenBank Accession No. NM_000127 for human EXT1 gene (paragraph 0036). Tokyo teaches a method for stably producing a virulent hand, foot and mouth disease virus comprising the steps of introducing genomic RNA of the virulent hand, foot and mouth disease virus into the host cell described above so as to obtain a cell producing the virus (paragraphs 0014, 0041). Tokyo teaches introduction of the genomic RNA of the virus to the host cells by transfection (paragraph 0043). Tokyo teaches the “virulent hand, foot and mouth disease virus strain” is a population of multiple causative virus particles of hand, foot and mouth disease (paragraph 0050). Therefore, Tokyo teaches providing host cells that do not express the EXT1 gene and introducing genomic RNA of the hand, foot and mouth disease virus into the host cell to obtain a cell producing the virus particles.
Tokyo does not teach that the inhibitor of EXT1 expression and/or activity is selected from the group consisting of an oligonucleotide having at least 75% identity, at least 90% identity or 100% identity with any one of sequences of SEQ ID NO: 35,36,39,43,44,48,50 and 52.
Before the effective filing date, Scadden et al. taught the discovery that small hairpin RNAs or short hairpin RNAs (shRNA) that target six proteins, when transduced into an isolated cell population of primary HSPCs, increased the colony forming capacity and the long-term culture forming capacity of the HSPCs. The transduced isolated cell population of primary HSPCs scored two- to five-fold higher in a standard methylcellulose colony forming cell assay (CFC) and over 100 fold higher in a standard long term culture initiating cell assay (LTC-IC). One of the six target proteins is exostoses 1 (EXT1) (paragraph 0006). Scadden et al. taught the RNAi agent is a shRNA that comprises a sequence selected from the group consisting of SEQ ID NOS: 2, 5, 8, 16, 17, and 18 (paragraph 0028, 0032) and teaches the RNAi agent inhibits gene expression of EXT1 and the RNAi agent comprises SEQ ID NO: 5 (paragraph 0104). Scadden et al. also teaches EXT1 of GenBank Accession No. NM_00127 (mRNA) (paragraph 0146), which is the same GenBank Accession No. of EXT1 taught by Tokyo. Table 1 on page lists shRNAs including shEXT1-3 of SEQ ID NO: 5 (Db) which is 100% identical to instant SEQ ID NO: 35 (Qy) as shown in the alignment below:
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Fig. 3B below shows results of experiments with the shEXT1 and that shEXT1-3 reduced expression of EXT1.
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Regarding claims 17 and 27, Tokyo teaches the cell is preferably an RD cell (reading on a eukaryotic cell as this is a rhabdosarcoma cell) and teaches preparation of the RD cells by genome editing using guide RNA targeting EXT1 gene (paragraphs 0013, 0072). Scadden et al. teach a cell population of primary HSPCs transduced with the shRNAs (paragraph 0006).
Regarding claims 25,33 and 34, Tokyo teaches harvesting the virulent hand, foot and mouth disease virus propagated by culturing the cell obtained by step 1 (paragraph 0041), and that the harvesting can be by a known method, for example by repeated sonication or freeze-thaw cycling of the culture solution containing the virus-producing cells so as to destroy the virus-producing cells, followed by removal of cell debris by centrifugation, and may be further purified by polyethylene glycol precipitation or density gradient ultracentrifugation (paragraph 0047). Tokyo teaches a step of culturing the cell obtained by the step of introducing genomic RNA of the hand, foot and mouth disease virus into the host cell described above so as to propagate the virus, followed by harvesting the virulent hand, foot and mouth disease virus propagated by culturing the cell obtained by the culturing step (paragraph 0041), and that the virus is released into the culture medium or accumulated inside the producing cells, and that the harvesting can be by a heretofore known method, for example by repeated sonication or freeze-thaw cycling of the culture solution containing the virus-producing cells so as to destroy the virus-producing cells, followed by removal of cell debris by centrifugation, and may be further purified by polyethylene glycol precipitation or density gradient ultracentrifugation (paragraph 0047).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have substituted the guide RNA or siRNA targeting the EXT1 gene and cell population used in the method of Tokyo with the EXT1 shRNA of SEQ ID NO: 5 and HSPC cell population of Scadden et al. as an alternative method of reducing expression of EXT1 and to increase the colony forming capacity and the long-term culture forming capacity of the HSPCs in the method of producing a virus with a reasonable expectation of success. There would be a reasonable expectation of success because both Tokyo and Scadden et al. teach polynucleotides that target the same gene, EXT1 and teach the same EXT1 Genbank Accession No. and Tokyo suggests siRNA or the like for reducing expression of EXT1, and this would amount to simple substitution of one known element for another to obtain predictable results. One of ordinary skill in the art would have been motivated to use an EXT1 shRNA, specifically the sequence of SEQ ID NO: 5 of Scadden et al. and the HSPC cells of Scadden et al. in the method of Tokyo as an alternative means to inhibit the expression of EXT1 as Scadden et al. taught short hairpin RNAs (shRNA) of EXT1 when transduced into an isolated cell population of primary HSPCs, increased the colony forming capacity and the long-term culture forming capacity of the HSPCs. The transduced isolated cell population of primary HSPCs scored two- to five-fold higher in a standard methylcellulose colony forming cell assay (CFC) and over 100 fold higher in a standard long term culture initiating cell assay (LTC-IC). Therefore, an ordinary artisan would expect that the shRNA of SEQ ID NO: 5 in the HSCPs of Scadden et al. which is taught as increasing colony forming capacity and long-term culture forming capacity when used in the hand, foot and mouth disease virus production method of Tokyo et al., would result in increased colony forming capacity of the HSPCs and would result in increased production of the hand, foot and mouth disease viruses.
Regarding claims 26-28 and 31-34, while Tokyo does not teach the specific recited order of the steps of transfecting the cell population with an oligonucleotide encoding the biological entity and then inhibiting EXT1 expression in the cell by using an inhibitor of EXT1 expression and/or activity, it would have been obvious to one of ordinary skill in the art to change the order in the production method as taught by Tokyo to provide a cell population, transfect the cell population with the genomic RNA of the hand, foot and mouth disease virus into the host cell, and then a step of inhibiting EXT1 expression in the HSPCs using the EXT1 shRNA of SEQ ID NO: 5 of Scadden et al. to arrive at claim 26 with a reasonable expectation of success. See MPEP 2144.04 IV. C. Changes in Sequence of Adding Ingredients, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). As applicant has claimed two different orders of steps in claims 16 and 26 and both processes arrive at the same result of producing a biological entity in a cell, there does not appear to be any criticality with the order of the steps since both orders are recited in the instant claims. Therefore, it would be obvious to perform the steps of transfecting a cell population with an oligonucleotide encoding the biological entity and inhibiting EXT1 expression in the cell using an inhibitor of EXT1 expression and/or activity in any order.
Accordingly, the limitations of claims 16-19,23-28 and 31-34 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Claims 16-19,23-28 and 31-34 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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