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 .
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.
Status of Claims
Claims 33-34, 37-40, 43, 45, 47, 51, 53, 61, 63, 66-68 and 75-81 are pending. Claims 61, 63, 66-68, and 75-79 are drawn to the nonelected inventions. Claims 33-34, 37-40, 43, 45, 47, 51, 53 and 80-81 are currently under examination.
Withdrawn Rejections
In view of Applicant’s amendments, the 35 U.S.C. 102 rejection is hereby withdrawn.
In view of Applicant’s amendments, the previous 35 U.S.C. 103 rejections are hereby withdrawn.
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.
Claim 81 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 81 recites “the solid gel does not comprise agarose” is new matter. Applicant in the response dated 10/16/2025 did not indicate where the support is from in the specification. Para. [0008] does not disclose such limitation. Meanwhile, Table A only indicated that BSA would produce a solid protein gel without agarose. Other media would require specific additional ingredients such as HistoGel TM (contains agarose) aide to form a pellet. Therefore, the recitation of “the solid gel does not comprise agarose” when in the presence of any serum albumin protein would introduce new matter because the specification fails to provide a direction or blaze marks to said limitations.
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 33-34, 37-40, 43, 45, 51, 53, and 80-81 are rejected under 35 U.S.C. 103 as being unpatentable over Frantz et al. (US2003/0157523A1, published 08/21/2003, IDS submitted 09/04/2024) in view of “Antonietta et al. (“A simple, rapid and inexpensive technique to bind small peptides to polystyrene surfaces for immunoenzymatic assays”, Journal of Immunological Methods, vol. 382, pgs. 216-219, published 06/07/2012), as evidenced by Zanini et al. (Environmental Health, 2012, vol. 11:59, pages 1-14, see 892 dated 07/16/2025).
With respect to claim 33, Frantz teaches biological microarrays for detecting the amount of and/or presence of a biological molecule in a biological sample. and the biological arrays of the invention comprise a solidified, sectionable matrix comprising a plurality of wells disposed therein and one or more biological samples disposed within the plurality of wells and the cellular microarrays of the invention may be a matrix material that is a temperature-sensitive material removable from the microarray leaving cellular biological material on the substrate surface (see abstract and Fig. 1) . Frantz teaches that the biological molecule comprises a polypeptide admixed in agarose with BSA to form an internal standard preparation that aids in analyzing an immunohistochemistry procedure performed on an array containing the protein internal standard preparation (see para. [0015]). Additionally, Frantz teaches biological or standard molecule of the internal standard can be embedded into any embedding material wherein the embedding material include agarose and BSA to help prevent a standard molecule from diffusing out of an internal standard preparation (see para. [0111]). Frantz teaches internal standard preparations are generally made by isolating one or more biological molecules with mixing with the embedding material and the internal standard preparation is solidified or form into a gel (see para. [0112]). Frantz further teaches embedding a specific protein molecule in agarose to form an internal standard preparation for use in an array so that the protein is retained throughout processing and a desired carrier protein such as BSA is incorporated into the agarose (see para. [0124]). In particular, Frantz teaches Her2/ErbB2 ECD protein was added to protein/water mixture and wherein the carrier protein such as BSA or other component such as naturally occurring or synthetic peptide sequence was incorporated into the agarose (see para. [0124]). Frantz further teaches the protein/agarose blocks were fixed with 10% neutral-buffered formalin (see para. [0125]). Frantz teaches that the intensity of the immunofluorescence signals resulting from the Her2/ErbB2 ECD internal standard preparation and the tissue samples were then correlated (see para. [0149]). Frantz teaches that the amount of Her2/ErbB2 receptor protein contained within the samples was quantified on the basis of the known amount of receptor protein in the internal standard preparations (see para. [0150]). Frantz teaches amino acid may be referred as synthetic amino acids (see paras. [0037], [0045] and [0049]). Frantz teaches synthetic peptide sequences can be incorporated into the agarose blocks by adding the desired amount of carrier protein (see para. [0124]). Frantz teaches the Her2/ErbB2 ECD protein in the protein/agarose internal standard preparation included approximately 650 amino acids from the N-terminus of the protein (see para. [0148]). Frantz teaches synthetic HER2/ErbB2 ECD standards (see para. [0150]). Table 4 teaches the antigens were raised against C-terminal peptides of the HER2 protein extracellular domain (see caption).
Meanwhile, Frantz does teach the fixation contains formaldehyde at 7.4% (e.g., see para. [0121]). Frantz further teaches the protein/agarose blocks were fixed with 10% neutral-buffered formalin (see para. [0125]). The evidentiary teachings of Zanini indicate that formalin contains tap water or buffers with formaldehyde (see page 2, left col., bottom of para. 1). Note that the claims are direct to a product and recitation of “after” is product-by-process. If the rejection above contains a structure having the crosslinking fixative and C-terminal cysteine crosslinked to the carrier protein, then it would meet the claimed structure of the invention. Also, note that the claim recites “the solid gel” but the structure of the solid antigen/carrier protein gel only requires an antigen that is crosslinked to a carrier protein. Based from the claims, the antigen crosslinked to a carrier protein would be the solid gel.
However, Frantz does not explicitly teach antigen cross-linked to the carrier protein wherein the C-terminal cysteine of the antigen is crosslinked to the carrier protein using a cysteine-reactive reagent.
Antonietta teaches peptides designed to display either an N or C terminal cysteine residue for maleimide-mediated conjugation with carrier proteins and in these conditions the peptides and carrier protein formed stable thioether bonds and allow for an optimal orientation of epitopes for subsequent antibody recognition (see pg. 217, left col., para. 3 and Fig. 1). Antonietta teaches ELSIA with maleimide-activated bovine serum albumin and the sulfhydryl-containing peptides are crosslinked, allowing their correct orientation and availability to antibody binding on polystyrene surfaces (see abstract). Antonietta teaches the efficiency of this DCLM (direct cross-linking method) and DCLM lead to OD values which were higher than that obtained by pre-coating conjugation (see go. 218, left col., last para.; and Fig. 1). Antonietta teaches DCLM is simpler, faster, and much more convenient alternatives to standard coupling protocols, allowing to save time and cut costs in ELISA applications (see pg. 218, right col., last para.). Antonietta teaches peptides coupled with this method show a known and predictable orientation, which allows a free interaction with antibodies both in vivo and in vitro (see pg. 217, left col., para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have crosslinked the polypeptide to the BSA as taught by Frantz with the maleimide-activated BSA as taught by Antonietta because Frantz teaches the presence of the polypeptides with BSA are for detection and Antonietta teaches that peptides that display C-terminal cysteine residue form a stable thioether bond to BSA carrier protein and allow an optimal orientation of binding affinity. It would have been obvious to the person to have used the C-terminus of polypeptide as taught by Frantz with a cysteine residue because Antonietta teaches the direction conjugation between cysteine and BSA is simple and the conjugation has a predictable orientation for optimal antigen detection.
The person would have a reasonable expectation of success incorporating maleimide activation group because it has been well recognized by Frantz and Antonietta to conjugate peptides to BSA carrier for antigen detection.
With respect to claim 34, Frantz teaches the 56 wells of the array recipient block are loaded with one or more biological samples to create a frozen biological array as described in Examples 7 and 9-11 and the frozen biological array is cut for slides into sections in a range of 6 µm to 12 µm thickness (see para. [0273]). Frantz teaches that the mold 140 may be any size and shape (see para. [0093]). However, the reference does not explicitly teach the solid gel has a thickness between about 30nm to about 50 µm. However, it would have been obvious to have the solid gel thickness to be the same or larger than the biological array to cover or coat the entire biological array.
With respect to claim 37, Frantz teaches a frozen biological array comprises a frozen matrix formed of a temperature-sensitive material (see para. [0009]). Frantz further teaches the matrix having a plurality of wells disposed therein, one or more internal standard preparations contained in some of the wells and the internal standard preparation comprises a standard molecule, such as biological, admixed in an embedding material and the embedding material differs from the matrix in physical and chemical properties such that the internal standard preparation will retain the standard molecule in the array (see para. [0014]). Frantz teaches the embedding material may be agarose or BSA or combination thereof (see bottom of para. [0060]).
With respect to claim 38, Frantz teaches the agarose block was allowed to solidify before being fixed in 10% formalin (NBF) and processed for embedding in paraffin and arrayed in paraffin blocks (see para. [0154]).
With respect to claim 39, Frantz teaches the temperature-sensitive matrix material comprises resin-polyvinyl alcohol and polyethylene glycol (see para. [0094]).
With respect to claim 40, Frantz teaches the biological array mounted on a planar platform or substrate (see para. [0071]).
With respect to claim 43, Frantz teaches the fixation contains formaldehyde at least about 1% (e.g., see para. [0121]).
With respect to claim 45, Frantz teaches anti-HER2 ECD antibody were pretreated with DAKO target retrieval solution (see closer to bottom of para. [0157]).
With respect to claim 51, Frantz teaches that the biological molecule comprises a polypeptide admixed in agarose with BSA to form an internal standard preparation that aids in analyzing an immunohistochemistry procedure performed on an array containing the protein internal standard preparation (see para. [0015], i.e., bovine serum albumin).
With respect to claim 53, Frantz teaches an internal standard block containing 5% BSA (see para. [0120]).
With respect to claim 80, Frantz teaches the protein/agarose blocks were fixed with 10% neutral-buffered formalin (see para. [0125]), which would read on an aldehyde-based fixative. The evidentiary teachings of Zanini indicate that formalin contains tap water or buffers with formaldehyde (see page 2, left col., bottom of para. 1).
With respect to claim 81, Frantz does not explicit teach the solid gel does not comprise agarose. Antonietta teaches that only BSA crosslinks with the peptide. Therefore, it would have been obvious to have only used BSA with peptide because peptides crosslinks to only BSA protein. The claim recites “the solid gel” but the structure of the solid antigen/carrier protein gel only requires an antigen that is crosslinked to a carrier protein.
Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Frantz et al. in view of Antonietta et al., as evidenced by Zanini et al, as applied to claim 33 above, and further in view of Metz et al. (“Identification of Formaldehyde-induced Modifications in Proteins”, Journal of Biological Chemistry, vol. 279, no. 8, pages 6235-6243, published 02/20/2004, see 892 dated 07/16/2025).
Frantz and Antonietta have been discussed above. Frantz does teach a general synthetic polypeptide antigen with BSA (see above). Frantz and Anthoietta teach C and N terminals on peptides. However, the references do not teach a tyrosine.
Metz teaches formaldehyde is a well-known cross-linking agent that can stabilize or immobilize proteins and the reactivity of each particular cross-link reaction as a function of the reaction conditions and identify new reaction products after incubation with formaldehyde (see abstract). Metz further teaches formaldehyde and glycine formed a Schiff-base adduct, which was rapidly attached to primary N-terminal amino groups, arginine, and tyrosine residues (see abstract). Metz teaches reactions of formaldehyde with mixtures of amino acids and derivatives to determine which amino acids can cross-link and it was demonstrated that formaldehyde reacts with amino and thiol groups of amino acids and forms methylol derivatives (see pg. 6235, right col., para. 2). Metz further teaches the reaction of formaldehyde with proteins starts with the formation of methylol adducts on amino groups and which can form cross-links with tyrosine (see Scheme 1 and caption).
It would have been obvious to a person of ordinary skill in the art to have produced the N-terminal of polypeptide as taught Frantz with tyrosine as taught by Metz because Frantz recognizes contacting a fixative solution comprising formaldehyde and Metz teaches effective N-terminal tyrosine crosslinks with proteins with formaldehyde. Meanwhile, the person would have reasonably expected success in using formaldehyde fixative with tyrosine because it has been well recognized by Metz that using formaldehyde to crosslink tyrosine and stabilize and immobilize protein.
Response to Arguments
Applicant’s arguments filed 10/16/2025 have been considered but are moot because Applicant’s amendments necessitated a new ground of rejection. However certain arguments will be addressed below.
Applicant argues on page 9 that the references do not teach “after the C-terminal cysteine is cross-linked to the carrier protein using a cysteine-reactive reagent”. Applicant further argues that claim 81 requires that the solid gel does not comprise agarose.
The arguments are not found persuasive for the following reasons. Note that the recitation of “after” in claim 33 is related to product by process limitation. If the rejection above contains a structure having the crosslinking fixative and C-terminal cysteine crosslinked to the carrier protein, then it would meet the claimed structure of the invention. Meanwhile, the limitations of the “solid gel” and “the antigen crosslinked to a carrier protein” are not distinctive in structure because claim 33 recites that “a solid antigen/carrier protein gel” only requires a purified antigen cross-linked to a carrier protein. With respect to claim 81, as stated above, although Frantz does not explicit teach the solid gel does not comprise agarose, it would have been obvious to have only used BSA with peptide because peptides crosslinks to only BSA protein, as taught by Antonietta.
Conclusion
No claim is allowed.
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.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678