Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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 1, 3-6, 8-9 and 11-20 are pending. Claim 3 is withdrawn. Claims 2, 7 and 10 are canceled. Claims 1, 4-6, 8-9 and 11-20 are under examination.
Election/Restrictions
Applicant previously elected the species of:
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New Rejections
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, 4-6, 8, 11 and 20 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 the limitations of “a derivative of rhodamine” and claim 8 recites the limitations of the derivative of rhodamine is a derivative of tetramethylrhodamine are unclear to the metes and bounds of what are the structures that constitute a derivative of rhodamine? If a derivative of a compound is another derivative of another compound, then what are the metes and bounds of the term derivative to rhodamine? Thus, the ordinary skill artisan would not understand the metes and bounds of a structure that is not a derivative of rhodamine. Claims 4-6, 8, 11 and 20 are rejected as being dependent from claim 1 and require the generic phrase derivative of rhodamine.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 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) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 1, 4-6, 8, 11 and 20 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Hong et al. (WO2012/003478A2, published 01/05/2012, see PTO-892 dated 03/12/2025).
With respect to claim 1, Hong teaches mass tags which can be specifically deposited at targets through enzymatic- catalyzed transformation (see abstract). Hong teaches the mass tag precursor is coupled to a tyramine or tyramine derivative via a linker such as an aliphatic or heteroaliphatic linker wherein the heteroaliphatic linkers are polyethylene glycol units having a formula PEGn where n ranges from 1 to 50 or 8 (e.g., PEG8) (see pg. 5, lines 24-30). Hong teaches that a mass tag precursor may be enzymatic converted into a mass tag such as a substrate for an enzyme (see pg. 32, lines 19-28). Hong teaches in Example 24 a compound which reads on the claimed compound wherein the latent reactive moiety is a substrate for peroxidase, a linker comprises at least an alkylene oxide group and the chromophore moiety is a derivative of rhodamine (see pg. 156 or below):
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It is noted that the recitation “for peroxidase” is directed to the intended use of the claimed compound, that does not affect the structure of the substrate (phenolic group). The intended use must result in a structural difference between the claimed substrate and the prior art’s substrate to patentably distinguish the claimed invention. Regardless, Hong’s phenolic group is capable of performing said intended use.
Additionally, the Hong’s CDO-PEG8-Arg-PL-Tyr compound (see above) would contain the claimed limitation of “a derivative of rhodamine”, the coumarin-based group is fused rings that has a heterocyclic group. Hong teaches Formula 4 (see bottom pg. 43 and top pg. 44), which would also read derivative of rhodamine.
Because the structure is unclear to the phrase “derivative of rhodamine”, the 102 rejection over Hong has been established (see above). Hong teaches in Example 24 a compound which reads on the claimed compound wherein the latent reactive moiety is a substrate for peroxidase, a linker comprises at least an alkylene oxide group and the chromophore moiety is a derivative of rhodamine (see pg. 156).
With respect to claims 4 and 20, the embodiment of Example 24 (see above) has an unsubstituted phenolic moiety.
With respect to claim 5, the embodiment of Example 24 (see above) has the unsubstituted phenolic moiety covalently coupled to the Linker through the amide bond (NH-C=O).
With respect to claim 6, the embodiment of Example 24 (see above) has the Linker comprises PEG8.
With respect to claim 8, Hong teaches Formula 4, which would read on a derivative of tetramethylrhodamine (see bottom pg. 43 and top pg. 44; and claim 103 on pg. 181, line 5-15).
Maintained Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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, 4-6, 8-9 and 11-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Hopman et al. (“Rapid Synthesis of Biotin-, Digoxigenin-, Trinitrophenyl-, and Fluorochrome-labeled Tyramides and Their Application for In Situ Hybridization Using CARD Amplification”, Journal of Histochemistry & Cytochemistry, vol. 46(6), pgs. 771-777, published 1998, see PTO-892 dated 03/12/2025) in view of Hong et al. (WO2012/003478A2, published 01/05/2012, see PTO-892 dated 03/12/2025), as evidenced by Sigma Aldrich (see PTO-892 for website, of record dated 03/12/2025).
With regards to claims 1, 6, 11-13 and 16-19, Hopman teaches the catalyzed reporter deposition (CARD) amplification procedure has been implemented successfully as a detection system such as in situ hybridization (ISH) (see pg. 771, left col., para. 1). Hopman teaches succinimidyl esters of rhodamine and aminomethylcoumarine acetic acid were coupled to tyramine (see abstract and pg. 771, right col., para. 2). Hopman further teaches the tyramide conjugate is based from rhodamine [5-(6)-carboxytetramethylrhodamine] succinimidyl coupling to tyramine to be utilized in the catalyzed reporter deposition (CARD) amplification and applied successfully in single- and multiple-target in situ hybridization (ISH) procedures to detect both repetitive and single-copy DNA target sequences in cell preparation with high efficiency (see abstract and pg. 772, left col., para. 1 of Materials and Methods). Hopman teaches NHS, N-hydroxysuccinimide (see pg. 772, left col., para. 1 of Materials and Methods). Hopman teaches tyramide conjugates is an easy method to prepare a variety of new substances for peroxidase cytochemistry because many active esters of fluorochromes or other haptens are commercially available (see pg. 776, right col., para. 2).
It is noted that the recitation “for peroxidase” is directed to the intended use of the claimed compound, which does not affect the structure of the compound. The intended use must result in a structural difference between the claimed compound and the prior art’s compound to patentable distinguish the claimed invention. Regardless, Hopman’s tyramide is capable of performing said intended use.
The evidentiary teachings of Sigma Aldrich indicate that 5-(6)-carboxytetramethylrhodamine of Hopman would read on the elected structure of chromophore moiety. Hopman teaches tyramine, which would read the phenolic moiety portion of the elected compound.
As stated above, Hopman teaches rhodamine and tyramine as the conjugate for peroxidase cytochemistry, but the reference does not teach a linker comprises at least an alkylene oxide (claims 1, 13, and 17), polyethene glycol (claims 6, 11 and 18) and in particular amine PEG8 (claims 12, 16, and 19; elected species). Additionally, Hopman does not teach a tyramine derivative that has one less CH2 group as claimed in the tyramine structure (claims 12, 16, and 19; elected species).
Hong teaches in situ hybridization (ISH) of human tissues in diseases states and ISH technologies are based on florescent and/or chromogenic signal target detection (see pg. 117, lines 5-10). Hong teaches enzymatic-catalyzed transformation (see abstract) and mass tag precursors are substrates for peroxidase (pg. 4, lines1-3). Hong teaches the optional linker is used to couple one moiety to a second moiety which covalently bind a mass tag precursor to a tyramine or a tyramine derivative and linkers are selected from any moiety capable of effectively coupling two moieties such as the mass tag precursor and a tyramine or tyramine derivative (see pg. 68, lines 20-28). Hong also teaches utilizing polyethylene glycol linker (PEG) having a general formula PEGn wherein n is typically 4-12 (see pg. 69, lines 7-10). Hong further teaches that an enzyme substrate and a mass tag precursor conjugate is for the enzyme to convert the mass target precursor conjugate into an activated species that is effectively coupled (e.g., covalently bound) to tyrosine moieties proximal to the target, such as at tyrosine moieties on the enzyme, on the specific binding moiety or on the target (see pg. 97, lines 22-27). Hong teaches the embodiments provide new methods for tissue analysis through the use of a wide class of mass tag precursors that provide effective and efficient methods for detection of particular target sites and the adoption of these methods in enzyme-linked immunoassays offers enhanced sensitivity and quantifiability in a multiplexing fashion (see pg. 8, lines 22-30). Hong recognizes chromophore may be rhodamine, fluorescein or coumarin dye (see pg. 181, claim 103). Hong also teaches in Example 24 a coumarin-based group is conjugated to PEG8 spacer (pg. 156).
Hong further teaches Formulas 34-35 (see pg. 68, left col., lines 8-15); and Formula 48 (see pg. 75, lines1-12). In particular, Hong teaches Formula 34 a tyramine or tyramine derivative (i.e., phenolic moiety, see pg. 68, lines 1-15). Hong further teaches the tyramine derivative has a Formula 35 wherein n is from 1 to 20 (see pg. 68, lines 15-20). Hong teaches the mass tag precursor is coupled to a tyramine or tyramine derivative via a linker such as an aliphatic or heteroaliphatic linker wherein the heteroaliphatic linkers are polyethylene glycol units having a formula PEGn where n ranges from 1 to 50 or 8 (e.g., PEG8) (see pg. 5, lines 24-30). Hong teaches in Example 24 with amine PEG8 (see pg. 156).
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to have modified the tyramine conjugated to rhodamine or 5-(6)-carboxytetramethylrhodamine for peroxidase cytochemistry of Hopman with a polyethylene glycol (PEG) spacer of Hong because Hong exemplifies polyethylene glycol spacers are used to effectively couple the coumarin-based group (e.g., derivative of rhodamine) to tyramine or derivatives thereof for peroxidase activity, as the enzyme converts the conjugate into an activated species that is covalently bound to tyrosine moieties proximal to the target and produces chromogenic signals. Meanwhile, Hong recognizes that PEG spacers are adjustable such as PEG4 to PEG20 in conjugating tyramine. Thus, it would have been obvious to the person to have conjugated tyramine or derivatives thereof to rhodamine [5-(6)-carboxytetramethylrhodamine] through an adjustable PEG spacer for increase sensitivity in enzyme-linked immunoassay because Hong teaches peroxidase has to activate or convert tyramine/tyramine derivatives before recognizing targets and sensitivity and quantifiability are dependent on the conjugate’s activation. Thus, the adjustability of the PEG spacer would optimize sensitivity and quantifiability with different targets.
With respect to the elected species (see above), it would have been obvious to have conjugated the tyramine derivative to 5-(6)-carboxytetramethylrhodamine through polyethylene glycol-8 (PEG8) for peroxidase activity because Hong exemplifies coumarin-based group being conjugated to the tyramine derivatives through the PEG8 spacer (e.g., see pg. 156, Example 24 above) and Hopman teaches rhodamine and coumarin-based group were alternatives to couple with tyramine. Additionally, Hong teaches PEG spacers are used to increase the sensitivity and quantifiability of the enzyme-linked assay.
As stated above, Hong does exemplify linkers having PEG8 (i.e., Example 24). In addition, adjustability of PEG spacers has been recognized in the art to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum space length for the conjugate as a result-effective variable in sensitivity and quantifiability for enzyme-linked immunoassays. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation" Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” Absent of unexpected results, it would have been obvious to the person of ordinary skill to discover the optimum PEG spacer length as a linker to conjugate tyramine derivative and 5-(6)-carboxytetramethylrhodamine for peroxidase activation because Hong teaches linking spacers are routinely optimizable for peroxidase activation of tyramine/tyramine derivative.
With respect to a tyramine derivative as part of the elected species
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, Hopman does not explicitly teach a tyramine derivative that has one CH2 chain less than a tyramine. However, Hopman does teach a homolog to the claimed compound. MPEP 2144.09 (II) has stated that compounds which are position isomers or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties and with a prima facie case of obviousness. Additionally, Hong does teach the claimed tyramine derivative (see Formula 35, pg. 68) is a recognized structure derived from tyramine. Therefore, it would have been obviousness to have made the elected tyramine derivative because the claimed tyramine derivative as elected is close in structural similarities to the tyramine and the structure has been recognized in the art as a derivative that is activated by peroxidase, as taught by Hong.
The person would have reasonably expected success in using alkylene oxide group (PEG) or PEG8 as the spacer to conjugate tyramine or derivatives thereof to rhodamine or 5-(6)-carboxytetramethylrhodamine because it has been well recognized in the art by Hopman and Hong to recognize coumarin-based group and rhodamine as alternatives for chromophore groups and Hong exemplifies the use of polyethylene glycol spacers to conjugate tyramine/tyramine derivatives for peroxidase.
With respect to claims 4-5 and 14-15, Hopman teaches tyramine (see abstract and pg. 772, left col., para. 1 of Materials and Methods), which would read on a substrate for peroxidase comprises an unsubstituted phenolic moiety and linked through a heteroatom moiety of O, N, and S.
With respect to claims 8-9, Hopman teaches rhodamine is 5-(and 6)-carboxytetramethylrhodamine (see pg. 772, left col., para. 1 of Materials and Methods), which would read on a rhodamine, derivative of rhodamine, derivative of tetramethylrhodamine, and carboxytetramethylrhodamine.
With respect to claims 13 and 17, see above for limitation of linker comprises a poly(alkylene oxide). Because the rejection above reads on the elected compound and the claimed compounds of claims 13 and 17, the chromophore would have been obvious to have provided the claimed function.
With respect to claim 20, Hopman teaches tyramine conjugates rhodamine succinimidyl ester (RHO-NHS) (see abstract and pg. 772, left col., para. 1 of Materials and Methods).
Response to Arguments
Applicant's arguments filed 03/17/2026 have been fully considered but they are not persuasive over the obviousness rejection of Hopman and Hong, as evidenced by Sigma Aldrich.
Applicant argues on page 6 that the missing rationale is especially significant because Hopman affirmatively teaches that directly coupling to tyramine is workable and successful. In fact, Hopman touts its synthetic approach as an “easy and fast method” for preparing such conjugates. Here, since Hopman already teaches a straightforward and effective detect-coupling route, the Patent Office must do more than identify a reference that discloses a PEG linker. Page 7, Applicant argues that the Office reliance on Hong also fails to show that Hong is reasonably pertinent to the problem faced by a skilled artisan starting from Hopman. Applicant further argues pages 7-8 that it is hindsight and the office has not established the required reasonable expectation of success. Applicant argues that neither Hopman nor Hong teaches or suggests the amended function of claims 13 and 17.
The arguments are not found persuasive because the claims are directed to a product claim. Meanwhile, both Hopman and Hong teach conjugate structures of chromophores (e.g., coumarin-based group or rhodamine) covalently attached to tyramine moiety for enzymatic reaction. In particular, Hong teaches that an enzyme substrate and a mass tag precursor conjugate is for the enzyme to convert the mass target precursor conjugate into an activated species that is effectively coupled (e.g., covalently bound) to tyrosine moieties proximal to the target, such as at tyrosine moieties on the enzyme, on the specific binding moiety or on the target (see above or pg. 97, lines 22-27). Thus, both Hopman and Hong teach conjugating well recognized chromophores such as rhodamine-based group and coumarin-based group to tyramine for enzymatic reaction. Meanwhile, Hong teaches the PEG8 linker is used to couple one moiety to a second moiety and linkers are selected for effective coupling of two moieties. As stated above, Example 24 of Hong recognizes the coumarin-based group attached to tyramine through PEG8 spacer. Thus, the combination of Hopman and Hong has a reasonably expected success and is not hindsight.
As evidenced by Hong, the reference recognized that linkers may be “optional” (see pg. 68, lines 20-28). In other words, the optional linker is not required to produce reaction. Thus, it has been recognized in the art that even “workable and successful” reactions (as argued by Applicant) would be enhanced by PEG8 linker because sensitivity and quantifiability are dependent on the conjugate’s activation.
With respect to amended claims 13 and 17, the combination of Hopman and Hong would read on the claimed structures and elected species. Because the references would produce the claimed compound, the chromophore would have been obvious and capable of producing the claimed function.
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
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