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 .
This application is a domestic application, filed 15 May 2023; and claims benefit as a CON of PCT/US2021/063185, filed 14 Dec 2021, which claims benefit of provisional application 63/127,269, filed 18 Dec 2020.
Claims 1-39 are pending in the current application. Claims 14-17, drawn to non-elected inventions, are withdrawn. Claims 1-13 and 18-39 are examined on the merits herein.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-13 and 18-39, in the reply filed on 03 Dec 2025 is acknowledged.
Claims 14-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03 Dec 2025.
Claim Objections
Claim 3 is objected to because of the following informalities: claim 3 at line 2 recites “amidite solution from the from the bed reactor …” (emphasis added) The duplicate “from the” should be deleted. Appropriate correction is required.
Claim 19 is objected to because of the following informalities: claim 19 recites a list of multiple limitations separated by semicolons. This list does not include conjunction such as “and”. Further, the absence of a conjunction might lead to confusion whether all items of the list are required (e.g. “and”), or whether the items of the list are alternatives and only one is required (e.g. “or”). Appropriate correction is required.
Claim 21 is objected to because of the following informalities: claim 21 at line 1 recites “wherein final segment of deblocking reagent solution is…” The text “final segment” should be preceded by an article such as “a”. Appropriate correction is required.
Claims 26-27 are objected to because of the following informalities: claims 26 and 27 each include multiple sentences. MPEP 608.01(m) provides “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).” 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 1-13 and 18-39 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 1 recites “A method of adding an oligonucleotide to a solid support within a bed reactor, the method comprising: removing a protecting group from the 5′ position of an oligonucleotide that is attached to the solid support; adding an activated amidite solution to the bed reactor, … and reacts at the 5′ position of the oligonucleotide…” (emphasis added) This claim language renders the claim indefinite because it is unclear if the method requires adding a pre-constructed oligonucleotide to the solid support, or if the method encompasses the stepwise adding of nucleoside phosphoramidite monomers to synthesize an oligonucleotide on the solid support. The specification does not clarify the meaning of this phrase or provide a limiting definition of this phrase. Dependent claims 2-13 and 18-39 incorporate the limitations of claim 1 and do not clarify the meaning of this language. The state of the prior art is represented by McCormac (WO 2004/055036 A1, published 01 July 2004, provided by Applicant in IDS filed 15 May 2023), which teaches the synthesis of an oligonucleotide is provided in which an oligonucleotide is assembled on a swellable solid support using the phosphoramidite approach (abstract). McCormac teaches the oligonucleotide is preferably prepared by coupling a nucleoside phosphoramidite with a nucleoside or oligonucleotide comprising a free hydroxy group (page 6, lines 30-35). McCormac teaches working examples of stepwise addition of nucleoside phosphoramidite monomers to prepare an oligonucleotide on a solid support (page 10, line 5 to page 11, line 15; page 16, lines 5-35). Therefore it is unclear if the claimed “adding” an oligonucleotide to a solid support encompasses “assembling” an oligonucleotide on a solid support according to the ordinary usage in the pertinent field of the art. For the purpose of examination, the phrase “adding an oligonucleotide to a solid support within a bed reactor” will be interpreted as encompassing “assembling an oligonucleotide that is attached to a solid support within a bed reactor”.
Claim 19 recites the limitation "the resin bed" in line 3 and “the resin particles” in line 4. There is insufficient antecedent basis for this limitation in the claims. Claim 19 depends from claims 5, 4, and 1. Claim 1 recites a “bed reactor”, however does not specify that the bed to be made of resin particles. Defining the bed reactor to comprise resin particles in either claim 19 or claim 1 would clarify this language.
Claim 20 recites the limitation “the resin bed” in line 4. There is insufficient antecedent basis for this limitation in the claims. Claim 20 depends from claims 19, 5, 4, and 1. Claim 1 recites a “bed reactor”, however does not specify that the bed to be made of resin particles. Defining the bed reactor to comprise resin particles in either claim 19 or claim 1 would clarify this language.
The term “some or all of the solvent washes are not fluidized” (emphasis added) in claim 23 is a relative term which renders the claim indefinite. The term “some” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear how many of the solvent washes are required not to be fluidized in order to fall within the scope of this claim. The specification provides description of “one or more” cycles or rounds of washing such as at paragraphs 47-48, 50, and 52 of the published application.
The term “the cleaner fraction of the wash solvent” (emphasis added) in claim 25 is a relative term which renders the claim indefinite. The term “cleaner fraction” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear how clean the fraction of the wash solvent is required to be in order to fall within the scope of this claim. The specification provides description of “one or more” cycles or rounds of washing, including reuse of the solutions, such as at paragraphs 47-48, 50, and 52 of the published application.
Claims 26 and 27 are generally narrative and indefinite, failing to conform with current U.S. practice regarding claims. Claim 26 describes an exemplary embodiment using language generally used in the specification. Claims 26 and 27 further include narrative descriptions of the function, effect, or advantages of the method rather than the structure or steps of the method. Further, regarding claim 26, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention.
The term “some of the cycles” in claim 31 is a relative term which renders the claim indefinite. The term “some” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear how many of the cycles the capping is omitted from is required to be in order to fall within the scope of this claim. The specification provides description of “one or more” cycles or rounds of the wash, such as at paragraphs 47-48, 50, and 52 of the published application.
The term “some of the reactions” in claim 32 is a relative term which renders the claim indefinite. The term “some” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear how many reactions are required to not be fluidized in order to fall within the scope of this claim. The specification provides description of “one or more” cycles or rounds of the wash, and in the text of fluidizing the reactor, such as at paragraphs 47-48, 50, and 52 of the published application.
Regarding claim 32, the phrase "for example" at line 2 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 30 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 30 recites the “method of claim 19, wherein the resin swelling is allowed to happen primarily during fluidization, which mitigates pressure drop…” This claim appears to describe the results of the steps performed in claim 19, and not a further limitation of the method such as a further structural limitation of the steps performed in claim 19 or an additional step to be performed. Therefore this claim 30 appears to be drawn to subject matter that is the same scope as claimed 19 from which it depends, and fails to further limit the subject matter. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 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.
Claims 1-2, 4-5, 7-8, 10 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by McCormac (WO 2004/055036 A1, published 01 July 2004, provided by Applicant in IDS filed 15 May 2023).
McCormac teaches the synthesis of an oligonucleotide is provided in which an oligonucleotide is assembled on a swellable solid support using the phosphoramidite approach (abstract). McCormac teaches the oligonucleotide is preferably prepared by coupling a nucleoside phosphoramidite with a nucleoside or oligonucleotide comprising a free hydroxy group (page 6, lines 30-35). The preferred phosphoramidites include a protecting group at the 5’ position (page 6, line 35 to page 7, line 25). The process according to the present invention may employ such process steps as are conventionally carried out for the solid-phase synthesis of oligonucleotides using phosphoramidite chemistry, including sulfurisation, oxidation and capping stages (page 7, line 25-30). McCormac teaches working examples of preparing a polystyrene resin comprising stepwise addition of nucleoside phosphoramidite monomers to prepare an oligonucleotide on a solid support in a jacketed solid phase reactor (page 10, line 5 to page 11, line 15), or a bed reactor composed of the polystyrene resin particles. In the synthesis cycle the protecting group at the 5’ position of the oligonucleotide is removed, amidite solution is added, the reactor was fluidized by bubbling of with mixture with N2 gas, sulfurization, oxidation, and capping, meeting limitations of claims 1-2, 4-5, 7-8, 10 and 14.
Claim Rejections - 35 USC § 103
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 3, 6, 9, 11, 13, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over McCormac (WO 2004/055036 A1, published 01 July 2004, provided by Applicant in IDS filed 15 May 2023) in view of Sinha (Sinha N.D., from Agrawal. S., ed., Methods in Molecular Biology, Vol. 20, Protocols for Oligonucleotides and Analogs, 1993, Humana Press Inc., p437-463, cited in PTO-892).
McCormac teaches as above as applied to claims 1-2, 4-5, 7-8, 10 and 14.
McCormac does not specifically teach the method comprising passing a solution through a filter located at the bottom of the bed reactor or adding nitrogen or another gas to the bottom of the reactor or some other type of agitation (claims 3, 6, 9, 11, 13, and 18).
Sinha teaches the state of the art regarding large-scale solid phase oligonucleotide synthesis before the time of the filing. Sinha teaches efforts to scale up the synthesis were to find the optimum condition to obtain almost the same quality of product as obtained from a lower-scale synthesis instrument without using such a large excess of reagents. Since the reactor or synthesis vessel used in this instrument is a batch-type reactor unlike a column-type reactor used for small-scale DNA synthesis where the entire amount of solid support is suspended into reaction solution to give efficient coupling, it is very essential to have proper fluidization of the large amount of supports. Fluidization in this approach is effected by bubbling dry gas (argon) through the bottom of a reactor, resulting in complete suspension of the support. (page 442, paragraphs 4-5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine McCormac in view of Sinha in order to optimize the design of the reactor or synthesis vessel through routine experimentation. One of ordinary skill in the art would have been motivated to combine McCormac in view of Sinha with a reasonable expectation of success because Sinha teaches the state of the art regarding large-scale solid phase oligonucleotide synthesis and teaches it is desired to scale up the synthesis to find the optimum condition to obtain almost the same quality of product as obtained from a lower-scale synthesis instrument, and teaches optimization such as bubbling dry gas through the bottom of a reactor, suggesting it would have been routine experimentation to optimize the physical location in the reactor where materials are delivered or removed.
Allowable Subject Matter
Claims 12, 19-29, and 31-39 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: The closest prior art is deemed to be McCormac (WO 2004/055036 A1, published 01 July 2004, provided by Applicant in IDS filed 15 May 2023) in view of Sinha (Sinha N.D., from Agrawal. S., ed., Methods in Molecular Biology, Vol. 20, Protocols for Oligonucleotides and Analogs, 1993, Humana Press Inc., p437-463, cited in PTO-892).
McCormac in view of Sinha teaches as above.
McCormac in view of Sinha does not specifically teach the method further comprising features such as wherein the upward and downward flow within the bed reactor is accomplished by adding pressure to the top of the reactor during the downward push and then releasing pressure from the top of the reactor during the upward push (claim 12) or wherein the wash solvent is drained out the bottom of the filter reactor prior to charging the next reagent; the reagent is drained out the bottom of the filter reactor prior to charging the next wash solvent; and the resin bed is mixed to suspend the resin particles in the reagents and/or wash solvents by inert gas bubbling or up and down flow of the liquid at selected times during selected reactions and/or washes in each cycle (claim 19).
It would not have been obvious to one of ordinary skill in the art to combine McCormac in view of Sinha in manner that arrives at the combined features of the claimed invention. As detailed above, the combined teachings of McCormac in view of Sinha suggest it would have been routine experimentation to optimize the physical location in the reactor where materials are delivered or removed based on the ordinary level skill in the art taught by Sinha. However, McCormac in view of Sinha does not provide sufficient guidance to arrive at the method comprising the combination of all features as in each of claims 12, 19-29, and 31-39 such as the features of claim 12 or 19 detailed above. Therefore the combined teachings of the prior art do not teach or fairly suggest each and every feature of the invention of claims 12, 19-29, and 31-39.
Conclusion
No claim is currently in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan S Lau whose telephone number is (571)270-3531. The examiner can normally be reached Monday-Friday 9a-5p Eastern.
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/JONATHAN S LAU/ Primary Examiner, Art Unit 1693