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 is the First Office Action on the Merits of US18/297,914 filed on 04/10/2023 which claims US priority benefit of US Provisional 63/330,677 filed on 04/13/2022.
Election/Restrictions
Applicant’s election without traverse of invention Group I (claims 1-13, and 21-23) in the reply filed on April 17, 2026 is acknowledged.
Claims 14-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 17, 2026.
Claims 1-23 are pending. Claims 14-20 are withdrawn.
Claims 1-13, and 21-23 are under examination.
Information Disclosure Statement
The IDS filed on 09/12/2023 has been considered by the examiner.
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.
Claims 3-6 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 3 recites the limitation "wherein the arginine residue” in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 3 depends from claim 1 which does not recite an arginine residue. Claim 2 recites that the amino acid residue is an arginine.
Claim 4 recites the limitation "wherein the arginine residue” in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 4 depends from claim 1 which does not recite an arginine residue. Claim 2 recites that the amino acid residue is an arginine.
Claim 5 is indefinite because it depends from claim 4 and is not remedial.
Claim 6 recites the limitation "wherein at least 50% of the arginine residue in a sample” in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 6 depends from claim 1 which does not recite an arginine residue in a sample. Claim 1 is silent regarding an arginine residue.
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 1-13, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al “Synthesis of 2-arylamino-5-formyl-pyrimidines from the bis(hexafluorophosphate) Arnold salt” Journal of Chemical Research published online March 23, 2020) in view of Gould et al (Toxicon, 1995 Vol 33, No. 2, pages 187-1995), in view of Gouliaev et al (US 20130281324 A1, published 10/24/2013).
Regarding claim 1, Lu et al discloses a method to functionalize a guanidine of compound 5a (shown just below), wherein the method comprises contacting compound 5a containing the guanidine with an Arnold Salt under conditions that result in formation of a formyl-substituted pyrimidine of Formula (I):
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wherein: X represents the remainder of the compound of 5a (the benzene ring), and each R is independently selected from methyl, ethyl, and propyl, or two R on the same N can optionally be taken together with the nitrogen to which they are attached to form a 4-6 membered ring. (See Table 2 reaction shown just below.)
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Regarding claim 2, Lu et al discloses that the reagent (see 5a just above) reacted with the Arnold salt to result in the formyl-substituted pyrimidine of Formula (I): but does not disclose the reagent is an amino acid residue being an arginine in a peptide.
Regarding claim 3, Lu et al discloses that the reagent is contacted with the Arnold Salt in a medium comprising an aqueous buffer and further comprising an organic cosolvent. (See Table 2 which shows a solvent of methanol:water at a 3:1 ratio.)
Regarding claim 4, Lu et al discloses that the reagent is contacted with the Arnold Salt in a medium at a temperature of 50°C which meets the limitation of between 40°C and 80°C.
Regarding claim 5, Lu et al does not explicitly discloses that the medium has a pH between 8 and 12. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP § 2144.05. The claimed limitation of a pH between 8 and 12 is considered optimization through routine experimentation, and would be obvious to one of ordinary skill in the art. Furthermore, a prima facie case of obviousness based on optimization may only be rebutted by evidence showing that the claimed range is critical, generally by proof that the claimed range achieves unexpected results relative to the prior art. See MPEP § 2144.05.
Further, regarding claim 6, in view of the rejection of claim 6 for being indefinite (see above), for purpose of applying art the limitation, absent evidence to the contrary, as presently written, Lu et al in view of Gould et al is construed to render obvious the limitation of at least 50% arginine residues in a sample being reacted with the Arnold Salt to produce the formyl pyrimidine. It would have been prima facie obvious for one of ordinary skill in the art to perform the reaction to result in a majority of arginine residues reacted for the rationale of efficiency.
Regarding claim 7, Lu et al discloses that the Arnold Salt is associated with a counterion selected from Br3-, ClO4-, PF6-, and BF4-. (See Figure 1 and Table 2 Reaction also shown above.)
The level of skill in the art was high before the effective filing date of the presently claimed invention.
However, Lu et al differs from the presently claimed method because while it teaches reacting an Arnold Salt with structure 5a as shown in Table 2:
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it does not disclose that the benzene of structure 5a may be substituted for the remaining side-chain of an arginine residue in a peptide/polypeptide sequence.
Gould et al disclose a method of chemical modification of the guanidine group at the terminal end of the side-chain of an arginine residue within a therapeutic polypeptide. Specifically, Gould et al disclose the modification of the Arg-14 of the sea anemone polypeptide anthopleurin-A in order to clarify the role of Arg-14 in its cardiac stimulatory activity. (See page 187.)
One of ordinary skill in the art would have been motivated to modify the method of Lu et al to functionalize a guanidine on the side chain of an amino acid residue, wherein the method comprises contacting a guanidine on the side chain of an amino acid residue within a polypeptide using an Arnold Salt under conditions that result in formation of a formyl-substituted pyrimidine of Formula (I), below, for the rationale of Gould et al to attach a conjugate to the arginine residue of a therapeutic polypeptide to study the therapeutic benefit of the arginine within the polypeptide.
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It would have been obvious to substitute the benzene of the Lu et al structure 5a (Table 2 and above) for the guanidine of the arginine side-chain in a peptide/polypeptide such as in the therapeutic cardiac polypeptide of Gould et al because the reactive part of each, being the guanidine,
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is identical.
In view of the high skill level in the art it is considered that one of ordinary skill in the art having the cited references before the effective filing date of the presently claimed invention would have had a reasonable expectation of success to substitute the benzene of the structure 5a (Table 2) of Lu et al for the remaining side-chain of an arginine residue including an arginine residue within a peptide/polypeptide to arrive at the presently claimed invention.
In addition, regarding claims 9-13, and 21-23, Lu et al in view of Gould et al differ from the presently claimed methods in further contacting the formyl pyrimidine (which contains a reactive aldehyde group) with a compound that comprises an aldehyde-reactive reaction handle having an -NH2 group and a target molecule, to facilitate linking the pyrimidine which is already attached to a peptide/polypeptide by the arginine side-chain to the target molecule (e.g., a polynucleotide) to form a conjugate.
Gouliaev et al discloses that it was known in the art to form a peptide-polynucleotide conjugate by reacting an available aldehyde with an aldehyde-reactive reaction handle having an -NH2 group, to form a conjugate linked to a target molecule, where the target molecule is a polynucleotide. Specifically, Gouliaev et al disclose that aldehyde tagged protein can readily be functionalized to attach linkers connected to target molecules of interest where such target molecules include polynucleotides (e.g., DNA, nucleic acid). (See entire document; Abstract; para 0022, 0290.)
Regarding claim 8, Gouliaev et al explicitly discloses the linker joined to a solid support. (See Abstract). In addition, Lu et al in view of Gould et al is construed to render obvious the limitation that the peptide is joined to a solid support in view of the broad description of solid support in the specification. For example, para 0072 of instant specification, states that the term “solid support” is construed to encompass any solid material to which macromolecules (e.g., peptide) can be “associated directly or indirectly, by any means known in the art, including covalent and non-covalent interactions”. A solid support may be a bead, a plastic surface, or a microtiter plate, an Eppendorf tube or a glass test tube. Thus, it is considered that the reaction of a peptide containing an arginine with a guanidine side chain with the Arnold Salt to form a formyl pyrimidine as rendered obvious over Lu et al and Gould et al would render obvious the reaction being performed in a vessel which meets the limitation of a solid support.
Further, regarding claim 9, Gouliaev et al discloses a step of contacting an aldehyde group with a compound that comprises a target molecule and an aldehyde-reactive reaction handle having an -NH₂ group, to form a conjugate to the molecule having the aldehyde group:
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;
where L¹ represents a linker, and Tm represents the target molecule. (See para 290, Examples of a latent reactive compound building block include, but are not limited to: nitro (which can be reduced to an amine), aryl methyl (which can be converted to aryl bromomethyl or to aryl carboxylic acid), olefin (which can undergo oxidative cleavage to afford an epoxide, an aldehyde or carboxylic acid), and the like. ).
Regarding claim 10, Gouliaev et al discloses that the conjugate is of the formula:
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wherein X represents the alkyl portion of the side chain of the arginine residue,
Y is O or NH, L2 represents a linker; and Tm represents the target molecule.
See para 0438:
[0438] The synthesis of a molecule according to the methods of the present invention can proceed via particular type(s) of coupling reaction(s), such as, but not limited to, one or more of the reactive group reactions cited herein above. In some embodiments, combinations of two or more reactive group reactions will occur, such as combinations of two or more of the reactive group reactions discussed above, or combinations of the reactions disclosed in Table 1. For example, reactive compound building blocks can be joined by a combination of amide bond formation (amino and carboxylic acid complementary groups) and reductive amination (amino and aldehyde or ketone complementary groups).
Regarding claim 11, Gouliaev et al discloses a further step comprising contacting the conjugate with a reducing agent to provide a conjugate of the formula:
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wherein X represents the alkyl portion of the side chain of the arginine residue,
Y is O or NH, and Tm represents the target molecule.
See para 0438:
[0438] The synthesis of a molecule according to the methods of the present invention can proceed via particular type(s) of coupling reaction(s), such as, but not limited to, one or more of the reactive group reactions cited herein above. In some embodiments, combinations of two or more reactive group reactions will occur, such as combinations of two or more of the reactive group reactions discussed above, or combinations of the reactions disclosed in Table 1. For example, reactive compound building blocks can be joined by a combination of amide bond formation (amino and carboxylic acid complementary groups) and reductive amination (amino and aldehyde or ketone complementary groups).
Regarding claim 12, Lu et al in view of Gould et al render obvious the limitation that X represents a peptide connected to the remainder of the conjugate through the alkyl portion of the side chain of an arginine residue of the peptide. (See above).
Regarding claim 13, Gouliaev et al discloses that target molecule (Tm) may be an identifier oligonucleotide which meets the limitation of a polynucleotide. (See Abstract.).
Regarding base claim 21, Lu et al in view of Gould et al renders obvious a method of attaching a peptide comprising at least one arginine residue to a formyl pyrimidine for reasons applied above. to a target molecule, the method comprising the steps of:
(a) contacting the at least one arginine residue with an Arnold Salt under conditions that result in formation of a formyl-substituted pyrimidine of Formula (I):
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wherein:
X represents the peptide connected through the at least one arginine residue, and
each R is independently selected from methyl, ethyl, and propyl,
or two R on the same N can optionally be taken together with the nitrogen to which they are attached to form a 4-6 membered ring for reasons provided above but do not disclose the step of contacting the formyl pyrimidine of Formula (I) with a compound that comprises the target molecule and an aldehyde-reactive reaction handle having an -NH₂ group, to form a conjugate of the formula of claim 21 or claim 23.
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wherein
L¹ represents a linker, and Tm represents the target molecule.
Regarding claim 22, Gouliaev et al discloses the target molecule may comprise a an identifier oligonucleotide which meets the limitation of a polynucleotide. (See Abstract.).
Regarding claim 23, Lu et al in view of Gould et al, in view of Gouliaev et al render obvious the formula:
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where Y is -O- or -NH-, L² represents a linker; and Tm represents the target molecule.
Gouliaev et al discloses that it was known in the art to form a peptide-polynucleotide conjugate by reacting an available aldehyde with an aldehyde-reactive reaction handle having an -NH2 group, to form a conjugate linked to a target molecule, where the target molecule is a polynucleotide. Specifically, Gouliaev et al disclose that aldehyde tagged protein can readily be functionalized to attach linkers connected to target molecules of interest where such target molecules include identifier oligonucleotides. (See entire document; Abstract; para 0022, 0290.)
One of ordinary skill in the art would have been motivated to use the aldehyde reactive group of the formyl pyrimidine (attached to a polypeptide of interest by the guanidine side chain of an arginine in such polypeptide) for the rationale of making an oligonucleotide identifier tag linked to such protein of interest in view of Gouliaeve et al because they disclose that such aldehyde groups are preferred reactive sites to form conjugates containing linkers and oligonucleotide tags (See para 0438).
It would have been obvious to do such in view of the cited references because the references disclose that such reagents and reactions were well-known in the art before the effective filing date of the presently claimed invention.
In view of the high skill in the art it is considered that one of ordinary skill in the art would have a reasonable expectation of success to use the Arnold Salt reaction of Lu et al to react the guanidine group of an arginine side chain of a therapeutic polypeptide of interest as shown in Gould et al to form a formylpyrimidine connected to such protein of interest and to then take advantage of the reactive aldehyde group on such pyrimidine to make a conjugate of a linker and an identifier oligonucleotide as shown in Gouliaeve et al to arrive at the presently claimed invention.
Conclusion
No claim is allowed.
Related prior art which may be applied in a future office action if appropriate:
James et al (US2022/014885 published May 12, 2022).
Chee et al (US Patent 11,513,126 issued 11/29/2022. US2020/0348308 published 11/5/2020; WO2019/089836 published 05/09/2019). Chee et al discloses conjugating polynucleotides to peptides. Chee et al discloses a method of attaching a conjugation reagent to a target molecule (reagents for labeling the DNA “recording tag” with coupling moieties for click chemistry coupling include alkyne-NHS reagents for lysine labeling, alkyne-benzophenone reagents for photoaffinity labeling, etc.
Chee et al (WO2017/192633 published 09/11/2017.
Balakrishnan et al (Chembiochem 2012 Jan 23: Vol 13(2): pages 259-270; IDS).
Ragan et al “Shock Sensitivity of a Vinamidinium Bis-Perchlorate Reagent and Demonstration of a Lower Energy Alternative” (Synlett 2000,No. 8, pages 1172-1174).
Mahnir et al (Toxicon 1989 vol 27, No 10, Abstract only).
Begum et al (J of Inorganic Biochem 2010 Vol 104, pages 177-484).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658
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