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 .
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.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/CN2020/117354, filed 09/24/2020. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 202010002171.3, filed on 01/02/2020 in China.
Status of the Claims
In the interest of compact prosecution, Applicant’s submission on 02/02/2026 has been accepted. However, Applicant is reminded of the proper format for amendments to the claims.
See MPEP 714. (c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived.
In the present case, claim 11 at line 1 has been amended in order to change the previous language “pathological collagen” to the present language “diseased collagen”. The limitation “pathological” should be shown with strike-thru and “diseased” should be shown as underlined.
Additionally, claims 18 and 19 show omitted claim language, however when compared to the last claims of record (08/27/2025), the language shown presently as strike-through was previously already omitted (this language was already absent from 08/27/2025).
As indicated above, in the interest of compact prosecution the amendments are accepted, however, further amendments should be properly annotated consistent with the markings as required (reflecting changes relative to the most recent entered amendments), indicated in the MPEP referenced above.
Claims 11, 16, 18 and 19 are pending; claims 1-10, 12-15, 17 and 20 are canceled; no claim are withdrawn. Claims 11, 16, 18 and 19 are examined below.
Withdrawn Objections/Rejections
The previous objection to the specification is withdrawn in response to Applicant’s amendments to the specification (amended to recite corresponding Sequence identifiers).
The previous objection to claim 11 for missing sequence identifier is withdrawn; see as indicated below the notice of non-compliant sequence disclosure set forth in response to Applicant’s remarks and amendments to the claims (that the sequence is not listed in the sequence listing and as such there is no identifier recited at the claims).
The previous objections to claims 13, 15 and 16 are withdrawn in response to Applicant’s amendments to the claims.
The previous rejection of claim 11 under 35 U.S.C. 112(b) is withdrawn in response to Applicant’s amendments to the claims (the claim amended in order to recite “diseased collagen” in place of “pathological”).
The previous rejections of claims 13 and 17 under 35 U.S.C. 112(b) are withdrawn in response to Applicant’s amendments to the claims.
SEQUENCE COMPLIANCE
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located at claim 11 (see previously the claim objected to for reciting a peptide sequence, as amended the claims recite (Gly-Hyp-Pro)n… the n is 10. In response to the previous objection, Applicant has indicated (remarks 02/02/2026) that there is no sequence listed for this sequence recited int eh claims in the sequence listing). Amino acid sequences having 4 or more residues that are both specifically defined and enumerated must be included in a sequence listing. The claimed peptide sequence is a 30 residue peptide.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
New Grounds of Objection/Rejection
Claim Objections
Claim 11 is objected to because of the following informalities: Claim 11 as amended recites “the signal molecule X is carboxyfluorescein FAM, the FAM refers to 6-carboxyfluorescein”, it is suggested that Applicant amend in order to merely recite “the signal molecule X is 6-carboxyfluoerescein” in order to be concise and improve clarity of the record.
Appropriate correction is required.
Maintained Grounds of Objection/Rejection
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.
Claim 16 is 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 16 recites at the preamble that the claimed method is “for preparing the peptide probe according to claim 11…that the methods include”, then the method recited as including steps (1)-(4). However, at recited step (1) “solid-phase synthesis of peptide resin (Gly-Hyp-Pro)n” does not clearly read as a method step itself, followed by steps (2)-(4) which read as solid phase synthesis method steps. As such, it is not clear if step (1) is part of the method, or if it is intended as describing that the method (from the preamble) is a solid phase synthesis method, the solid phase synthesis method then comprising steps following what is recited at step (1) (i.e., the method is a solid phase synthesis method, comprising steps recited at labeled steps (2)-(4)).
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.
Claim(s) 11 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al., Direct Detection of collagenous proteins by fluorescently labeled collagen mimetic peptides, Bioconjug. Chem., 24(1), (2013), p. 9-16 in view of Goodman et al., WO9710106A2, Schlumpf et al., WO2018/187530A1 and ThermoFisher. (2015). Peptide Design. Internet Archive, https://web.archive.org/web/20151016190442/https://www.thermofisher.com/us/en/home/life-science/protein-biology/protein-biology-learning-center/protein-biology-resource-library/pierce-protein-methods/peptide-design.html. [Accessed 11/13/2025].
Li et al. teach a peptide probe (CMP, see abstract, (GlyProHyp)9) including a signal molecule modified at the N-terminal region of the peptide probe (see page 3, paragraph 2, Li further teach a fluorescein dye (5(6)-carboxyfluorescein), the probe for detection of diseased collagen (denatured collagen see abstract, e.g., identification of pathologic conditions in fibrotic liver tissues, abstract; page 3, paragraph 3; page 4, paragraph 3; page 5, paragraph 1). Li suggest that single stranded collagen mimetic peptides (CMP, sequence GPO, with 5-10 repeats), can bind unfolded collagen chains through the formation of collagen-CMP heterotrimeric complexes, the interaction originating from the unique triple helical structure of the collagens, and the inherently strong triple helical folding propensity of the CMPs (see page 2, second full paragraph). Li et al. report convenient staining of collagen based on triple helix forming peptide probe that can directly detect collagenous proteins (page 2, beginning of second full paragraph). Li teach their study as validating the use of fluorescently labeled collagen mimetic peptides for direct and efficient detection of Hyp rich collagenous proteins and immunostaining; Li teaching fluorescent CMP is an excellent alternative to collagen antibodies for detection fibrous collagens (see page 6, second full paragraph).
Li et al. teach a collagen mimetic peptide comprising a tripeptide with glycine, proline and hydroxyproline, repeating the tripeptide 6-10 times (creating a helical structure), however fails to teach the claimed sequence (Gly-Hyp-Pro)n.
Further, Li and the cited art does teach attachment of the fluorophore through a flexible linker (GGG), however, fails to teach the flexible linker Ahx, where Ahx is aminohexanoic acid.
Similar to Li et al., Goodman et al. teach a synthetic collagen in triple helical conformation comprising amino acid chains of repeating timers of highly populated collagen sequences (abstract). See Goodman et al. at claims 24, 30 and 31, template-assembled amino acid chains which assume a stable triple helical conformation, Goodman et al. teaching repeating tripeptides, including Gly-Hyp-Pro.
Schlumpf et al. teach collagen mimetic peptides (CMPs, similarly to Li and Goodman et al.), conjugated with either therapeutic compounds and/or more diagnostic compounds (para [0022], conjugates). Schlumpf teach (similar to Li) the conjugates for treating and diagnosing disease, disorders or conditions (para [0022]). Regarding the CMPs, see Schlumpf et al. teach as an example, a 21-mer comprising seven repeats of a three amino acid sequences, see specifically SEQ ID NO: 2. SEQ ID NO. 2 is a 21 amino acid residue peptide, repeating the timer Hyp-Pro-Gly seven times, but further this peptide comprises at least 6 repeats of Gly-Hyp-Pro, as claimed (SEQ ID NO. 2 of Schlumpf, reads on “peptide sequence (Gly-Hyp-Pro)n where n is the integer 6”).
ThermoFisher teach the linker Ahx (aminohexanoic acid) as a common hydrophobic spacer for linking peptides with dyes or tags (see end of page 4).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the trimeric peptide sequence of Li et al., by substituting Li’s repeating sequence of Gly-Pro-Hyp for the sequence Gly-Hyp-Pro as taught by Goodman et al. Specifically, the prior art, Li et al., contained the base concept, namely the concept of a collagen mimetic peptide conjugate for binding and detecting collagen, including diseased collagen (related to diagnoses, see Li et al., as cited in detail above), which the concept of Li et al. differed from that which is claimed not by the content of the CMP, but rather the order of the residues in the sequence (Li’s sequence comprising the trimeric residue order GPO, rather than the claimed GOP). However, both GPO and GOP presented as repeating structures were recognized in the art as forming stable triple helical structures (see Goodman et al., cited in detail above), and further helical structure containing this repeating structure were known and recognized in the art as capable of forming conjugate structures for binding/detection of collagenous proteins (see similarly to Li, also is Schlumpf, SEQ ID NO. 2 specifically comprising repeats of the sequence GOP as claimed, SEQ ID NO. 2 taught as a CMP conjugate structure).
As a result, one having ordinary skill in the art would have found it obvious to have used the trimeric GOP sequence in place of the GPO sequence of Li (repeating this trimeric structure 6-10 times), and the results would have predictably been a triple helical structure capable of serving as a labeled conjugate for binding and detecting collagen, as in Li et al. One having ordinary skill in the art would have had a reasonable expectation of success because sequences containing this repeat trimer were already known to those skill in the art suitable as CMP conjugate species (for example, SEQ ID NO. 2 of Schlumpf), and because compositionally, this trimer contains the same composition, in terms of the same amino acids, merely in a different order, however that different order of residues also recognized in the prior art as similarly forming a stable helical conformation (Goodman), just like Li’s repeated sequence.
Further, regarding the limitation that n is 10, Li et al. does teach between 6-10 repeats of the trimeric sequence, it would have obvious to have arrived at 10 repeats by selecting from the appropriate number of repeats as taught by Li et al. One having ordinary skill would have a reasonable expectation of success because Li teach a range of anywhere from 6-10 as an appropriate number of repeats (see Li’s conjugate comprising between 6-10).
Further, the general conditions in terms of the number of trimeric repeats are taught by the prior art (for example Li), Li teaching sufficient structure (repeats) to form a stable triple helical structure. Goodman also teach their trimeric repeats forming stable triple helical structure. Based on the cited prior art, which teaches the general structure consistent with that claimed, it does not appear to be inventive to discover the optimum or workable range of suitable repeats. See MPEP 2144.05. It would have been further prima facie obvious to have optimized the number of repeats, namely by selecting from and trying numbers of repeats, as taught by Li, to arrive at the optimum workable number for achieving a stable, triple helical structure. One having ordinary skill in the art would have had a reasonable expectation of success given the similarities (discussed previously above) between the sequences as taught by Li as compared to Goodman (and further Schlumpf).
Additionally, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have modified Li et al. and the cited prior art, in order to have provided Ahx as the linker/spacer in place of GGG, since both are prior art recognized spacer species known for conjugation of a peptide to a dye (ThermoFisher). Further one having ordinary skill in the art would have a reasonable expectation of success because ThermoFisher teach Ahx as an art recognized common species for this purpose, further one would have an expectation of success because ThermoFisher specifically teach this spacer as able to link peptide with a dye (label species).
Regarding claim 18, as Li and the cited prior art reads on a peptide probe that is a detection reagent as claimed.
Claim(s) 19 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. in view of Goodman et al., Schlumpf et al. and ThermoFisher, as applied to claim 11 above, and further in view of Zuk et al., US Patent 4,208,479.
Li et al. and the cited prior art teach a peptide probe substantially as claimed, however Li et al. fails to teach providing the peptide probe in the form of a kit (fails to use the language “detection kit”, as presently claimed at claim 19).
However, the advantages of packaging together necessary reagents in kit form were well known in the art at the time of the invention.
For example, Zuk et al. teach that in performing assays it is a matter of substantial convenience, as well as providing significant enhancement in accuracy to provide the reagents combined in a kit (column 22, lines 20-68).
Therefore, it would have been further prima facie obvious to one of ordinary skill in the art to package together the peptide probe reagent of Li et al. and the cited art in the form of a kit for convenience, improvement in accuracy, and/or for the purpose of commercial sale.
Claim(s) 16 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al., in view of Goodman et al., Schlumpf et al., ThermoFisher, Xiao et al. CN107266562A (provided with machine obtained English Translation obtained via PE2E Search) and Lawrence et al., WO2007/021661A2.
Regarding claim 16, Li et al. teach peptide probe substantially as recited at claim 11 (see Li et al. in view of the prior art, as cited in detail previously above).
Regarding Li et al., Li teach peptides prepared using solid-phase peptide synthesis (SPPS) using Fmoc/HBTU chemistry (see page 3, paragraph 2).
Li et al. teach a collagen mimetic peptide comprising a tripeptide with glycine, proline and hydroxyproline, repeating the tripeptide 6-10 times (creating a helical structure), however fails to teach the claimed sequence (Gly-Hyp-Pro)n. Further, Li et al. is silent as to the details of their solid phase synthesis.
Goodman et al. and Schlumpf et al. are as cited in detail previously above.
Regarding the peptide probe of claim 11, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified Li et al. with Goodman, Schlumpf and ThermoFisher for the reasons as discussed in detail previously above (see as above at claim 11, it would have been obvious to have modified Li’s probe for the reasons as indicated).
Further as referenced above, Li is silent as to their solid phase peptide synthesis protocol (silent as to the method steps/conditions of their solid phase peptide synthesis protocol).
See however, Xiao et al. teaching an example of solid phase peptide synthesis of collagen probes, the method of producing (synthesizing) said probes, comprising solid synthesis of peptide resin, the method comprising 4eq of signal molecule, HOBt and HBTU dissolved in DMF, activated at low temperature for 10-30 min (see translation page 3, “specific method of polypeptide solid phase synthesis in step (2)”), 6eq DIEA into solution to form a mixture. See further, the method comprising adding mixture to resin, reacting 1-6 hours (see Xiao at page 3, a-c). After washing, Xiao teach treating the peptide resin with cutting fluid (see step f, trifluoroacetic acid:TIS:water, ratio of 90:5:5) for 1-6 hours, see further adding ice, diethyl ether, obtaining pure peptide (peptide probe). (See also claim 4 of Xiao).
Regarding presently claimed step (4), the claim differs from the protocol as in Xiao in that the claim recites a narrower time range (claim recites 2-4 hours) for treating with cutting fluid, whereas Xiao recites a period of 1-6 hours. The claimed range lies within the prior art cited range, it would have been prima facie obvious to one having ordinary skill in the art to have arrived at the claimed narrow range out of routine optimization, namely by selecting and trying times within the prior art disclosed duration taught by Xiao in order to uncover the optimum workable duration for treatment with cutting solution (to determine the duration that achieves the optimum result in terms of produced peptide probe). One having ordinary skill would have a reasonable expectation of success because the prior art taught the broader range of 1-6 hours, which the claimed range is substantially similar, merely slightly narrower than the time taught by Xiao. See further MPEP 2144.05, in the case where the claimed ranges lies inside ranges disclosed by the prior art, a prima facie case of obviousness exists.
Xiao’s protocol further differs from that which is claimed (referring to present claim step 3) in that Xiao is teaching reacting the mixture (corresponding to that recited at claimed step 2) for 1-6 hours, instead of the claimed 12-48 hours, and Xiao’s protocol fails to teach this reaction step performed “away from light”.
However, see also for example, Lawrence, which also refer to solid phase synthesis protocols for synthesis of peptoid ligands (peptide mimics), Lawrence teach synthesis using standard solid phase peptide synthesis protocol, Lawrence teach incubation in the dark overnight (which reads on the lower end of the claimed range), using cutting solution consistent with Xiao (TFA:TIS:water), at a ratio of 95:2.5:2.5, to deprotect and release from resin.
It would have been further prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have relied on incubation in the dark over night as an obvious matter of applying a known technique to a known method (solid phase peptide synthesis techniques), specifically because Lawrence is another example of procedure that is considered standard solid phase synthesis procedure (see Lawrence). It would have been obvious to have arrived at the claimed incubation duration (for example, overnight) in the dark by applying techniques known in the art for such methods (solid phase synthesis methods), namely by performing method steps such as incubating using art recognized incubation conditions known for achieving successful synthesis. The results would have been predictable, specifically one having ordinary skill in the art would have a reasonable expectation of success using art recognized techniques for achieving synthesis.
Even further, for the same reasons as applied above (regarding incubation conditions), it would have been obvious to have applied the cutting solution as a ratio of 95:2.5:2.5 as taught by Lawrence (obvious matter of applying a known technique for achieving an art recognized, predictable result, one expecting success because Lawrence teach their protocol as standard for solid phase peptide synthesis). Additionally, the modification would have been an obvious matter of a simple substitution one known ratio for another, the prior art that is Lawrence is teaching the same cutting solution (TFA:TIS:water) as Xiao, both teaching the same solution for the same purpose. One having ordinary skill in the art would have a reasonable expectation of success considering both references are using the solution for the same purpose, as part of solid phase peptide synthesis, and further considering the prior art supports this is standard method conditions (Lawrence, teaching standard protocol).
Response to Arguments
Applicant's arguments filed 02/02/2026 have been fully considered but they are not persuasive for the following reasons.
Regarding remarks at page 12, as indicated in detail above, the previous objection to the specification is withdrawn in response to applicant’s amendment to the specification.
Regarding the previous objection to claim 11 and remarks at page 12, see as indicated above, the previous objection is withdrawn in response to the amendment to the claims. However, see as indicated in detail above, the claim is not in compliance with sequence requirements.
Regarding previous objections to claims 13, 15 and 16, see the objections are withdrawn in response to Applicant’s amendments to the claims.
Further, regarding remarks at page 12-13, see as indicated above, previous rejection of claim 11 under 35 U.S.C. 112(b) is withdrawn in response to Applicant’s amendments to the claims (the claim amended in order to recite “diseased collagen” in place of “pathological”), and the previous rejections of claims 13 and 17 under 35 U.S.C. 112(b) are withdrawn in response to Applicant’s amendments to the claims.
Regarding remarks specific to the previous rejection of claim 16 under 35 U.S.C. 112(b) (remarks pages 12-13), at remarks Applicant indicates the listed step (1) is one step in the method, namely the synthesis of the peptide resin using solid phase synthesis, and steps 2-4 are steps of activating the signal molecule, loading the signal molecule on the peptide resin and obtaining the peptide probe after obtaining the peptide resin in step (1). The rejection is maintained, the subsequent steps (2-4, activating, loading and obtaining) appear to be steps involved in the solid phase synthesis. It is not clear what is meant by remarks that this first step is synthesis of the peptide resin, for example, is it intended as anchoring of the peptide to the resin, as this would be one step in a solid phase synthesis procedure.
Regarding the rejection of claims under 35 U.S.C. 103, Applicant argues that the claimed peptide is distinct from that as taught by Li in that the present invention claims GOP (different from GPO of Li), the present claims repeating the structure 10 times, the claimed signal molecule linked to the sequence via Ahx. Applicant argues compared to that of Li, the claimed invention exhibits significant single-stranded stability, is easy to prepare, and does not require pre-treatment steps such as heating before use, completely avoiding the potential damage to sample.
Applicant argues (remarks page 12) that Goodman is teaching a synthetic collagen with a triple-helix conformation, Applicant argues that Goodman’s research is primarily focused on synthesizing collagen with triple helix formation, emphasizing structure and synthesis methods of collagen itself (page 13), rather than disclosing the repeating tripeptide could serve as a probe for detecting collagen. Applicant is asserting that Goodman’s publication represents a completely different technical field and application direction (remarks page 13). Applicant asserts that the present invention is transforming the known repeating tri-peptide structure into a probe with specific detection functions and optimizing its structure to meet the requirements for detection pathological collagen. However, in response, this argument by Applicant (emphasized above) acknowledges that the repeating tri-peptide structure is a known structure. It is noted that the claimed invention at claim 11 is a product invention, and is not, for example, recited as a method for detection of pathological collagen, i.e., is not a method, comprising active steps of using the known product in an unknown order of active method steps, for example.
It is maintained that the claimed product is obvious over the cited combination of the prior art. Specifically, the prior art, Li et al., contained the base concept, namely the concept of a collagen mimetic peptide conjugate for binding and detecting collagen, including diseased collagen (related to diagnoses, see Li et al., as cited in detail above), which the concept of Li et al. differed from that which is claimed not by the content of the CMP, but rather the order of the residues in the sequence (Li’s sequence comprising the trimeric residue order GPO, rather than the claimed GOP). However, both GPO and GOP presented as repeating structures were recognized in the prior art as forming stable triple helical structures (see Goodman et al., cited in detail above), and further helical structure containing this repeating structure were known and recognized in the art as capable of forming conjugate structures for binding/detection of collagenous proteins (see similarly to Li, also is Schlumpf, SEQ ID NO. 2 specifically comprising repeats of the sequence GOP as claimed, SEQ ID NO. 2 taught as a CMP conjugate structure). As such, Applicant’s arguments that Goodman et al. is a completely different technical field and application direction, that Goodman provides a contrary technical inspiration because their objective was to synthesize repeating tripeptides with triple helix formation, are not persuasive.
At remarks page 13 Applicant argues that when the polypeptide sequence itself forma tripe-helix structure, it loses its binding ability to pathological collagen, referring to colorimetric experiments in Example 6 of the specification, where probes GPP-10, GPO-10, and GOO-10 lose their binding ability to collagen due to formation of the triple helix structure. Applicant argues as such, based on Li combined with Goodman, a person would expect the peptide is prone for forming triple helix structure, making it unstable as a collagen detection probe and prone to losing its binding ability to pathological collagen.
However, it is not readily clear that Applicant’s data supports the modification as indicated above from GPO to GOP would be expected unsuitable as a probe for diseased collagen, particularly since the prior art, teaching the tripeptide GPO as at Li is teaching this peptide suitable as a probe (Li et al. teach a peptide probe (CMP, see abstract, (GlyProHyp)9) including a signal molecule modified at the N-terminal region of the peptide probe (see page 3, paragraph 2, Li further teach a fluorescein dye (5(6)-carboxyfluorescein), the probe for detection of diseased collagen (denatured collagen see abstract, e.g., identification of pathologic conditions in fibrotic liver tissues, abstract; page 3, paragraph 3; page 4, paragraph 3; page 5, paragraph 1). While Applicant’s data at Example 6 does appear to support, based on Applicant’s experimental conditions, that there could be a loss of binding at 0 degrees, this does not persuasively overcome the prior art which does support the claimed product is obvious over the cited prior art. For example, the argument appears to argue specific parameters in using the claimed peptide probe, that under certain conditions (regarding temperature), the peptide is not usable as a probe, however, the claimed invention is not directed to an unobvious or uncommon combination of method steps, rather the claimed invention is directed to a product.
Applicant further argues (page 13) that Goodman does not disclose a number or repeats, that Li is reciting a broad range of repeats (6-10). This argument is not persuasive, 6-10 repeats is a finite list of art recognized suitable alternatives, it is maintained, according to the direction as provided in the cited art (such as Li), that it would be obvious to try the options set forth by the finite list of suitable alternatives as disclosed by the prior art (6-10 is only 5 possible repeat formations to try). Applicant’s own remarks (page 12, second line from the bottom), support their conclusion of 10 is a result of optimization of experimental conditions.
At remarks page 12, Applicant argues the citation of Schlumpf et al., asserting that Schlumpf introduced a pharmaceutical composition for treating disease, arguing that in contrast, the core of the present invention lies in developing a polypeptide probe for detection pathological collagen, i.e., the field of diagnostic reagents. This argument is not persuasive, see Schlumpf teach (similar to Li) the conjugates for treating and diagnosing disease, disorders or conditions (para [0022]).
Applicant also argues that although the sequence OPG repeated 7 times does contain the sequence GOP repeated 6 times, that the performance of the OPG repeated 7 times cannot equate with that of the sequence GOP 6 times, applicant suggesting that if the additional portion of the OPG repeat sequence interferes with binding to collagen or alters the spatial conformation of the probe, it may lead to decreased detection sensitivity or loss of specificity. However, in response, this argument is also not persuasive as there is not evidence that persuasively establishes that the additional portion would interfere as hypothetically suggested by Applicant (see Applicant’s remarks indicating “If the additional portion”).
Applicant further argues that the prior art does not support it would have been obvious to have modified the linker GGG with Ahx, that although both belong to the category of recognized spacers used to bind peptides to signal molecules, they exhibit significant differences in chemical structure and physical properties an biological activity, however, this is not persuasive as Applicant has provided no such evidence to support that such asserted differences are known or expected to interfere with the common recognized ability of both to link peptides with signal molecules. Further, Applicant has provided no evidence that the different spacers would impact performance differently (referring to remarks page 12). Rather, based on the cited art, one having ordinary skill would expect success using either.
At remarks page 13 Applicant argues that Experimental research has revealed that if the Ahx linker is not used and the signal molecule FAM is directly connected to the sequence, it may lead to alterations, however, this argument does not persuasively support it would not be obvious to merely use another art recognized spacer, recognized for the same purpose. The combination of the cited art is not omitting the spacer, rather is merely making the case that it would have been obvious to use the spacer Ahx. The argument that it “may” lead to alterations is a suggestion not supported by any factual evidence.
Applicant further cites Cai et al. as supportive evidence of criticality and unexpected functional performance of the claimed product (remarks page 12). Applicant argues the cited publication supports that the claimed probe maintains single-stranded monomer conformation even at 0 degrees C, unlike conventional probes at low temperature. Applicant argues that the operational advantage, that conventional probes only achieve effective staining when preheated, that both unheated and preheated, F-GOP-10 provided strong fluorescence tissue staining.
In response, it is noted that the publication is by present inventors, and appears consistent with arguments referencing the specification as indicated above. In the present case, although Applicant’s publication and specification presents data specific to peptide as in Li, Li also supports their peptide (GPO) usable as a detection probe- the distinction between Li et al.’s results and Applicant’s results appears to have to do with how the probe is used (i.e., the method of using), and as noted above, the claimed invention is a product invention (not a method of using the product). The combination of the cited art does support it would be obvious to modify Li et al.’s peptide in order to provide the sequence GOP. For these reasons, Applicant’s arguments that the claimed product has an operational advantage (i.e., specific to the use of the claimed probe), is not persuasive that the claimed probe itself is not obvious.
Applicant’s arguments regarding the probe length (n is 10, remarks page 12) are not persuasive for reasons as indicated above, it is not unobvious to rely on a length of 10 considering the prior art specifically indicates 10 as suitable (Li et al. teach 6-10).
Applicant further provides Declaration under Rule 37 CFR 1.132 by inventor, Professor Xiangdong Cai (hereinafter referred to as the Cai Declaration). The Cai declaration reiterates the same details as presented in arguments referred to above. The Cai declaration is acknowledged, and similar to arguments above, lists the probe structures prepared and tested, and presents conformation results at 0 degrees C (monomer versus triple helix), tissue staining results with and without heat treatment and selective recognition of pathological collagen. The data and arguments are not persuasive for the reasons as discussed in detail above. While the arguments and data may support the unexpected nature regarding the ability to use the claimed probes for detection without heat treatment (methods of using the probe under specific conditions), they are not persuasive that the claimed probe itself (as a product that is usable as a probe) is unexpected. The distinction, based on Applicant’s arguments and data, appears to be specific to the use of the probe under conditions without heat (which is a consideration specific to a method of using the probe, not the probe itself; for example, one would expect success using the probe under conventional conditions in the art, for example when heated). Nonetheless, it is also the case that Li is not limited to heat activation, but also suggest light activation of caged CMP probes.
For all of these reasons, Applicant’s arguments are not persuasive and the claims are rejected as indicated in detail above.
Conclusion
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.
Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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