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 .
Priority
This application claims priority to provisional application 62/491245, filed on 27 April 2017, and is a divisional of 16/608796, filed on 25 October 2019. The effective filing date is 27 April 2017.
Information Disclosure Statement
The information disclosure statements (IDS), filed on 28 July 2025, 12 May 2025, and 05 February 2024 were considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-45 are the original claims. In the amendment of 05 February 2024, claims 6, 10, 11, 15, 16, 18, 20, 21, 24, 28-41, 43, and 44 were cancelled, and claims 7, 9, 12, 14, 17, 19, 27, and 42 were amended. Claims 1-5, 7-9, 12-14, 17, 19, 22, 23, 25-27, 42, and 35 are pending and the subject of this office action.
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.
Claims 1-4, 7, 8, 13, 27, 42, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over WO2015158868 A2 (herein Germeroth) in view of Singh R, et al. (1996) Formation of N-substituted 2-iminothiolanes when amino groups in proteins and peptides are modified by 2-iminothiolane. Anal Biochem. 1996 Apr 5;236(1):114-25 (herein Singh).
In regard to claim 1, Germeroth relates to in vitro methods of expanding population of cells, comprising contact between a population of cells and a multimerization reagent (Abstract). In this publication, Germeroth teaches that cross-linked oligomers or polymers of streptavidin or streptavidin muteins may be generated by introducing, in a first step, thiol groups into the streptavidin, through the use of Traut’s reagent (2-iminothiolane) (Relevant to claims 3, 13, and 45) ([0077]). In a second step, available amino groups are taught to be activated, through the addition of thiol-reactive functional groups, through a reaction comprising heterobifunctional crosslinkers, such as SMCC or SMPH (Relevant to claims 2, 7, and 8) ([0077]). The two reaction products are then mixed, under conditions favorable for the promotion of a reaction between the added thiol groups and the maleimide group of the added crosslinker ([0077]).
Germeroth does not teach that the oligomeric particle reagents, produced by the thiol-maleimide reaction, are in contact with a stabilizing agent. Singh teaches this deficiency.
Singh relates to a study investigating the stability of thiol adducts on proteins treated with 2-iminothiolane (Abstract). Singh teaches that the reaction of an amine with 2-iminothiolane is rapid and initially forms a thiol adduct, but this adduct is unstable and decays to a N-substituted iminothiolane adduct, which lacks a thiol group (Discussion and Scheme 2). It is taught that by incubating a protein containing N-substituted iminothiolane adducts with hydroxylamine, under mild conditions, one can regenerate the original amine (Relevant to instant claim 27) (Discussion).
It would have been obvious to one skilled in the art to combine the method of crosslinking streptavidin molecules using maleimide-thiol crosslinking, taught by Germeroth, with the method of removing N-substituted iminothiolane from proteins thiolated with 2-iminothiolane, taught by Singh. As taught by Singh, the product of a reaction of 2-iminothiolane with the amine groups of a protein is unstable and decays into a adduct, that is not suitable for subsequent crosslinking reactions. The presence of non-native chemical moieties, such as N-substituted iminiothiolanes, caused by the inherent instability 2-iminothiolane – amine reaction product, provides ample motivation to combine the teachings. Furthermore, hydroxylamine was taught to be capable of removing these undesirable non-native moieties under mild conditions (pH 7.5), which further enhances the motivation for selecting it as a stabilizing agent, as these mild conditions are unlikely to denature the oligomeric particle reagents (Disccusion).
In regard to claim 4, the claims establish efficacy limitations of the invention described in claim 1. MPEP 2121 states: “When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability.” Since each element of claim 1 is taught by the prior art, efficacy a similar to that illustrated in the instant application and set-out in claim 1 is presumed (see In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980)).
In regard to claim 42, Germeroth discloses exemplary embodiments of oligomeric particles comprising a streptavidin mutein molecules, in which the amino acid sequence comprises “Val44- Thr45-Ala46-Arg47 (SEQ ID NO: 62) or Ile44 -Gly45 -Ala46-Arg47 (SEQ ID NO: 63) at sequence positions corresponding to positions 44 to 47 with reference to positions in streptavidin in the sequence of amino acids set forth in SEQ ID NO: 1” ([0609]). These muteins are identical to those referenced in instant claim 42.
Claims 5, 9, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over WO2015158868 A2 (herein Germeroth) and Singh R, et al. (1996) Formation of N-substituted 2-iminothiolanes when amino groups in proteins and peptides are modified by 2-iminothiolane. Anal Biochem. 1996 Apr 5;236(1):114-25 (herein Singh) in view of the instructions for Pierce Premium Grade Sulfo-SMCC (Catalog No PG82085), © 2013 Thermo Fisher Scientific Inc (herein Pierce).
In regard to claims 5, 9, and 25, Germeroth and Singh teach a method for producing an oligomeric particle reagent comprising streptavidin, as discussed above for the 35 U.S.C. 103 rejection of claims 1-3, 7, 8, 13, 23, 27, 42, and 45. Germeroth and Singh do not teach specific reaction conditions for the production of a plurality of streptavidin or streptavidin mutein molecules, a comprising a thiol-reactive functional group. Pierce teaches these deficiencies.
Pierce provides a general protocol for the conjugation reaction of a heterobifunctional crosslinker, sulfo-SMCC, with a protein/peptide (Whole document). In the general protocol, Pierce teaches that the reaction between the sulfo-SMCC reagent and the protein/peptide is to be carried out at a pH of 7.2 (see definition of conjugation buffer), at room temperature, and using an incubation time of 30 minutes (Relevant to instant claim 9) (Section B. Protocol). Pierce also provides guidance regarding the crosslinker : protein molar ratio for the reaction, and teaches that the ratio decreases as protein concentration increases (Section B. Protocol and Table 1). At a protein concentration of 10 mg/mL, a molar excess of 5:1 is recommended, which falls within the range cited by instant claim 5. The protocol also teaches the removal of excess activating agent (sulfo-SMCC) though the use of a desalting column (Relevant to instant claim 25) (Section B. Protocol).
It would have been obvious to combine the teachings of Germeroth and Singh (method for producing an oligomeric particle reagent comprising streptavidin) with the technical guidance provided by Pierce. Although, Germeroth does disclose a method for producing oligomeric particle reagents, comprising streptavidin or streptavidin muteins, the disclosure is silent in regard to technical details. It would have been obvious, to one skilled in the art, to use the protocol provided by Pierce, a supplier of the reagents disclosed in the method, taught by Germeroth. A supplier of reagents has a strong incentive to optimize protocols, using said reagent, in that by providing an effective protocol, the supplier ensures customer satisfaction. Therefore, using the supplier’s protocol has a high likelihood of success.
Claims 12, 14, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over WO2015158868 A2 (herein Germeroth) and Singh R, et al. (1996) Formation of N-substituted 2-iminothiolanes when amino groups in proteins and peptides are modified by 2-iminothiolane. Anal Biochem. 1996 Apr 5;236(1):114-25 (herein Singh) in view of the instructions for Traut’s Reagent (Catalog No 26101), © 2012 Thermo Fisher Scientific Inc (herein Thermo).
In regard to claims 12, 14, and 25, Germeroth and Singh teach a method for producing an oligomeric particle reagent comprising streptavidin, as discussed above for the 35 U.S.C. 103 rejection of claims 1-3, 7, 8, 13, 23, 27, 42, and 45. Germeroth and Singh do not teach specific reaction conditions for the production of a plurality of streptavidin or streptavidin mutein molecules, a comprising a thiol functional group. Thermo teaches these deficiencies.
Thermo provides a general protocol for the thiolation of proteins using Traut’s reagent (2-iminothiolane) (Whole document). In the general protocol, Thermo teaches that the reaction between Traut’s reagent and the protein/peptide is to be carried out at a pH of 8.0, at room temperature, and using an incubation time of 1 hour (Relevant to instant claim 14) (Procedure for Thiolation of Protein with Traut’s Reagent). Pierce also provides guidance regarding the molar ratio of Traut’s reagent to protein (Traut’s reagent : Protein) for the reaction, with a range of 2:1 to 20:1 being recommended (Procedure for Thiolation of Protein with Traut’s Reagent). An example is provided, in which the ratio used was 10:1. This example falls within the range cited by instant claim 12. The protocol also teaches the removal of excess thiolating agent (2-iminothiolane) though the use of a desalting column (Relevant to instant claim 25).
It would have been obvious to combine the teachings of Germeroth and Singh (method for producing an oligomeric particle reagent comprising streptavidin) with the technical guidance provided by Thermo. Although, Germeroth does disclose a method for producing oligomeric particle reagents, comprising streptavidin or streptavidin muteins, the disclosure is silent in regard to technical details. It would have been obvious, to one skilled in the art, to use the protocol provided by Thermo, a supplier of the reagents disclosed in the method, taught by Germeroth. A supplier of reagents has a strong incentive to optimize protocols, using said reagent, in that by providing an effective protocol, the supplier ensures customer satisfaction. Therefore, using the supplier’s protocol has a high likelihood of success.
Claims 17, 19, 22, 23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over WO2015158868 A2 (herein Germeroth) and Singh R, et al. (1996) Formation of N-substituted 2-iminothiolanes when amino groups in proteins and peptides are modified by 2-iminothiolane. Anal Biochem. 1996 Apr 5;236(1):114-25 (herein Singh) in view of the instructions for Protein-Protein Crosslinking Kit (Catalog No P6305), © 2011 Thermo Fisher Scientific Inc (herein Fisher).
In regard to claims 17, 19, 22, and 26, Germeroth and Singh teach a method for producing an oligomeric particle reagent comprising streptavidin, as discussed above for the 35 U.S.C. 103 rejection of claims 1-3, 7, 8, 13, 23, 27, 42, and 45. Germeroth and Singh do not teach specific reaction conditions for the production a particle composition, comprising oligomeric particle reagents comprising a plurality of streptavidin or streptavidin mutein molecules. Fisher teaches these deficiencies.
Fisher provides a general protocol for the crosslinking of 2 proteins, one of which comprises thiol functional groups and the other thiol-reactive functional groups (i.e. maleimide-derivatives) (Whole document). In the general protocol, Fisher teaches that the reaction between the two protein components is to be carried out, immediately after exposure of the thiol groups (i.e. after completion of the thiolation reaction or removal of thiol capping moieties), at a pH of 7.5, at room temperature, and using an incubation time of 3 hour (Relevant to instant claims 19 and 26) (Crosslinking the Protein X–SH and Protein Y–Maleimide). Fisher also teaches a 1:1 molar ratio of the two protein reagents (Relevant to instant claim 17). Additionally, the protocol also teaches the use of NEM to quench the reaction (Relevant to instant claim 22).
It would have been obvious to combine the teachings of Germeroth and Singh (method for producing an oligomeric particle reagent comprising streptavidin) with the technical guidance provided by Fisher. Although, Germeroth does disclose a method for producing oligomeric particle reagents, comprising streptavidin or streptavidin muteins, the disclosure is silent in regard to technical details. It would have been obvious, to one skilled in the art, to use the protocol provided by Fisher, a supplier of a kit comprising reagents needed to perform the method, taught by Germeroth. A supplier of reagents has a strong incentive to optimize protocols, using said reagent, in that by providing an effective protocol, the supplier ensures customer satisfaction. Therefore, using the supplier’s protocol has a high likelihood of success.
In regard to claim 23, Singh and Fisher teach that the thiol group resulting from 2-iminithiolane reactions (Singh- Discussion and Scheme 2) and maleimide derivatives are unstable (Fisher- Creating a Maleimide Derivative of Protein Y). Based on these teachings, it would have been obvious, to one skilled in the art, to limit the time before combining thiolated streptavidin and thiol-reactive streptavidin reagents, as both are unstable. The most obvious means of limiting degradation would be to produce both streptavidin reagents simultaneously, thus limiting the amount of time the reagents are allowed to degrade. Support for this comes Fisher’s teaching of immediate progression from thiol-exposure towards the mixture of both reagents (the thiolated component and maleimide-derived protein) (Deprotecting the Thiolated Protein X-4.5). Taken in context with Singh’s teachings, regarding thiol group instability, the instruction to immediately proceed towards the mixing of reagents, shows that timeliness is a method for limiting degradation. With this established, the simultaneous preparation of both reagents, referenced in instant claim 23, becomes obvious, due to the shared unstable nature of the both reagents.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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