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 .
Acknowledgement of Receipt
Applicant’s Response, filed 7/22/2026, in reply to the Office Action mailed 5/19/2022, is acknowledged and has been entered. Claims 14 and 20 have been amended. Claims 37 and 38 are newly added. Claims 14-29 and 32-38 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. New grounds of rejection are set forth herein, necessitated by claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 14-17, 21-25, 37 and 38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zheng et al. (US 2017/0319719), as evidenced by Zhao et al. (CCS Chem., 2021, 3, 678–693).
Zheng discloses a nanovesicle having a bilayer comprising a saturated first phospholipid and no more than about 15 molar % of a second phospholipid covalently conjugated to a J-aggregate forming dye (paragraph 0006).
In an aspect, there is provided a method of monitoring temperature at a target site comprising: providing the nanovesicle of any one of claims 1-20 at the target site, and monitoring a photoacoustic signal at the target site (paragraph 0009).
Preferably, the dye is selected from the group consisting of pseudoisocyanine, merocyanine, bis(2,4,6-trihydroxyphenyl)squaraine, Zn-chlorin, tetrtakis(4-sulfonatophenyl)-porphyrin, bacteriochlorin, antimony(III)-phthalocyanine, copper phthalocyanine and perylene bismide, Hypericin, subphtalocyanine, preferably bacteriochlorin. Further preferably, the second phospholipid covalently conjugated to the J-aggregate forming dye is bacteriochlorophyll-lipid (paragraph 0028).
In some embodiments, the dye is conjugated to the glycerol group on the second phospholipid by a carbon chain linker of 0 to 20 carbons (paragraph 0035).
Exemplary J-nanoparticles comprise Bchl-lipid, PEG2000-DPPE and host lipids, and photoacoustic imaging is performed (paragraph 0046-0054).
With regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
With regard to claim 37, at least pseudoisocyanine and merocyanine are cyanine dyes. With regard to claim 38, at least pseudoisocyanine, merocyanine, hypericin, etc. are specifically preferred dyes, which are bonded to a lipid (functional moiety).
Normally, only one reference should be used in making a rejection under 35 U.S.C. 102. However, a 35 U.S.C. 102 rejection over multiple references has been held to be proper when the extra references are cited to: (A) Prove the primary reference contains an "enabled disclosure;" (B) Explain the meaning of a term used in the primary reference; or (C) Show that a characteristic not disclosed in the reference is inherent. For example, "to serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill." Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749 (Fed. Cir. 1991). See MPEP 2131.01.
Zhao discloses that supramolecular assembly of organic dye compounds with J-aggregation leads to a red-shifted absorption spectrum that greatly facilitates the construction of near-infrared (NIR) materials (abstract). As a total consequence, the relative energy between the chromophore aggregates and monomers, that is, [EF (k) − ES1 ], crucially relies on the chromophore geometries. When JCoul is negative, the excitation energy of the aggregates is smaller than the monomers, resulting in a red-shifted absorption; the aggregates are slipped “head-to-tail” and are defined as J-aggregates (page 679).
Accordingly, in the instant case, Zhao is included to show that J-aggregate forming dyes, as disclosed by Zheng, are necessarily capable of “head-to-tail” orientation.
Response to arguments
Applicant argues that claim 14 as amended, now recites "an MJ conjugate of Formula I: MJ-E-D, wherein MJ is a modified J-aggregate containing stable head-tail arrangements of dye molecules held together by non-covalent interactions." The specification provides clear guidance as to what a "modified J-aggregate" means in the context of the claims. Applicant asserts that first, the specification explicitly defines a J-aggregate in terms well understood by those of ordinary skill in the art: "cyanine dye J-aggregates, which are stable head-tail arrangements of dye molecules held together by non-covalent interactions like van der Waals and electrostatic interactions" (paragraph [0007]). This is the universally accepted definition of a J-aggregate - it is a supramolecular assembly of dye molecules held together by non-covalent intermolecular forces, not a lipid-based structure. Applicant asserts that second, the specification makes clear that the “modified" J-aggregate (MJ) is itself such a dye assembly that has been functionalized and that third, paragraph [0096] states: "Modified J-aggregates (MJs) described herein are designed to provide improved photoacoustic probes of various sizes, including nanoscale. Functional moieties, including but not limited to a drug, a protein, an antibody or a payload may be attached to the MJs either directly or via a linker to form MJ conjugates". This confirms that MJs are standalone entities to which functional moieties are attached - the MJ is a structurally discrete aggregate component within the conjugate. Applicant further notes that fourth, the specification's examples confirm the MJ is a discrete particle.
Applicant’s arguments have been fully considered but are not persuasive. With regard to the argument that cyanine dye J-aggregates are stable head-tail arrangements of dye molecules held together by non-covalent interactions like van der Waals and electrostatic interactions, it is noted that Zhao is included to show that J-aggregate forming dyes, as disclosed by Zheng, by definition as J-aggregates are necessarily capable of “head-to-tail” orientation. With regard to the argument wherein the modified J-aggregate (MJ) is itself such a dye assembly that has been functionalized, it is noted that a J-aggregate forming dye as disclosed by Zheng is modified in that it has been conjugated to a phospholipid. With regard to the arguments wherein the MJ is designed to provide improved photoacoustic probes of various sizes, including nanoscale; Functional moieties, including but not limited to a drug, a protein, an antibody or a payload may be attached to the MJs either directly or via a linker to form MJ conjugates and that the MJ is a discrete particle, it is respectfully submitted that the claims are not commensurate in scope with the arguments. The claims do not recite the identity of the functional moiety or recite a particulate form. Further, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant further argues that Zheng's nanovesicle is structurally distinct from the claimed MJ. Applicant asserts that Zheng discloses a nanovesicle having a bilayer comprising a saturated first phospholipid and a second phospholipid covalently conjugated to a J-aggregate forming dye (paragraph [0006]). This is fundamentally different from the claimed MJ in at least four respects. Applicant asserts that Zheng's structure is a phospholipid bilayer vesicle (a liposome-type structure). The claimed MJ is a self-assembled aggregate of dye molecules. Applicant asserts that in Zheng, the dye is covalently bonded to a phospholipid. In the claimed MJ, the dye molecules are held together by non-covalent interactions (van der Waals and electrostatic forces), as defined in the specification. Applicant further argues that Zheng's structure is primarily composed of phospholipids, with dye accounting for no more than ~15 molar% of the second phospholipid component (claim 3); while claimed MJ is an aggregate whose structural scaffold is formed by dye molecules assembled through non-covalent interactions. Applicant asserts that in Zheng, the dye is a minor component covalently tethered to a lipid scaffold. In the present claims, the dye molecules are the scaffold - they self-assemble into the MJ particle.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to asserted differences in structure, it is respectfully submitted that Zheng’s Figure 2 specifically shows J-aggregation in formulations containing 5%-50% Bchl-lipid. It is noted that by definition J-aggregates are necessarily capable of “head-to-tail” orientation. With regard to the argument that in Zheng the dye is covalently bonded to a phospholipid, it is noted that the instant claims allow for bonding to a functional moiety. Bchl-lipid forms J-aggregates in Zheng. With regard to arguments directed to relative amount of components, it is noted that the arguments are not commensurate in scope with the claims which do not require amounts of components. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant further argues that claim 14 requires the structural formula MJ-E-D, where E is a linker or bond connecting the modified J-aggregate (MJ) to a functional moiety (D). In the present claims, E connects the surface of the self-assembled dye particle to an external functional moiety (see Scheme 1 showing copper-free click chemistry between ICG-azide on the particle surface and DBCO-PEG-Biotin). Applicant contends that Zheng does not connect a J-aggregate to an external functional moiety. The structural context is entirely different. In the present claims, the MJ particle exists as a complete self-assembled entity, and E then bridges from that particle to the functional moiety D.
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted, as set forth above, that Zheng teaches a J-aggregate forming dye conjugated to a lipid, i.e. via a bond or linker. The lipid is a functional moiety. Zheng readily teaches that J-aggregates were observed, see e.g. Figure 2 or Figure 9. Accordingly, the disclosure of Zheng meets the limitations of the instant claims.
Applicant argues that Zheng does not disclose the functional moiety "D". Applicant argues that the Examiner has not identified what element in Zheng corresponds to the "functional moiety" D. Claim 14 requires D to be a distinct functional moiety connected to MJ via linker E. The specification provides extensive guidance on what D encompasses: streptavidin, biotin, RGD, etc.
Applicant’s arguments have been fully considered but are not persuasive. The J-aggregate forming dye is linked to a lipid. It is noted that the instant specification describes in paragraph 0096 that the functional moiety may be “including but not limited to a drug, a protein, an antibody or a payload”. As such the arguments are not commensurate in scope with the claims.
Applicant further argues that for the product-by-process claims, the relevant question is whether the product disclosed in Zheng is the same as the product recited in the claims and that as demonstrated above, it is not. Applicant further notes that Zheng does not disclose a cyanine.
Applicant’s arguments have been fully considered but are not persuasive. With regard to product-by-process limitations it is respectfully submitted that the disclosure of Zheng meets the structural limitations of the instant claims, as set forth above. As such it is considered that the rejection of the product-by-process claims is proper. It is further noted that at least pseudoisocyanine and merocyanine are encompassed with a class of cyanine dyes.
Claim(s) 14-20 and 23-26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sasaki et al. (Chem Eur J., 2020, 26(35), 7840-6), as evidenced by Zhao et al. (CCS Chem., 2021, 3, 678–693).
Sasaki discloses design of a porphyrin monomer 6N3 bearing azidohexyl chains as long, yet rigid, side chains (Figure 1). Upon cooling a hot solution of 6N3 in MCH, nanoparticles 6N3NP formed. After equilibration of this solution for several hours at room temperature, we observed a change in the solution color, suggesting a change in the porphyrin stacking mode. Concomitantly, considerable precipitation occurred, which hampered absorption spectral measurements of the Soret band. Optical microscopy appeared to show that the precipitates were not 1D structures. We prepared a drop-cast film of this material… a prominent split Soret band was observed for the film of 6N3, indicating the formation of short-slipping J-aggregates, as in the case of 61NS. To our delight, supramolecular nano sheets consisting of 6N3 with uniform thickness (4.1 nm) were visualized by atomic force microscopy (AFM). Thus, a systematic understanding of the relationship between the monomer structure and the self-assembly energy landscapes enabled us to design anew monomer for 2D supramolecular polymerization (pages 7842-3).
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The presence of azide groups in the self-assembled structures is advantageous because of their ability to undergo functionalization by click chemistry. Boron dipyrromethene (BODIPY)was chosen because of its high fluorescence quantum yield, and we performed a catalyst-free click reaction using BDP-DBCO. See also Figure 4.
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Furthermore, confocal laser scanning microscopy (CLSM) images (Figure 4i–k) confirmed that the red fluorescent nano sheet had been successfully coupled to the green fluorescent BODIPY dye. The ability to post-functionalize by using covalent chemistry on self-assembled structures could permit the fabrication of more challenging nanostructures (page 7844).
Accordingly, modified j-aggregate comprising an azide is linked to a functional group. With regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Normally, only one reference should be used in making a rejection under 35 U.S.C. 102. However, a 35 U.S.C. 102 rejection over multiple references has been held to be proper when the extra references are cited to: (A) Prove the primary reference contains an "enabled disclosure;" (B) Explain the meaning of a term used in the primary reference; or (C) Show that a characteristic not disclosed in the reference is inherent. For example, "to serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill." Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749 (Fed. Cir. 1991). See MPEP 2131.01.
Zhao discloses that supramolecular assembly of organic dye compounds with J-aggregation leads to a red-shifted absorption spectrum that greatly facilitates the construction of near-infrared (NIR) materials (abstract). As a total consequence, the relative energy between the chromophore aggregates and monomers, that is, [EF (k) − ES1 ], crucially relies on the chromophore geometries. When JCoul is negative, the excitation energy of the aggregates is smaller than the monomers, resulting in a red-shifted absorption; the aggregates are slipped “head-to-tail” and are defined as J-aggregates (page 679).
Accordingly, in the instant case, Zhao is included to show that J-aggregate forming dyes, as disclosed by Sasaki, are necessarily capable of “head-to-tail” orientation.
Response to arguments
Applicant argues that Sasaki does not disclose the conjugate formula MJ-E-D. Applicant asserts that in the claims, the MJ is formed first (by co-aggregation of a J-aggregate forming dye with a functionalized J-aggregate forming dye), and then a linker and functional moiety are conjugated to the MJ. The result is a discrete tripartite conjugate: a J-aggregate particle bearing a functional moiety through a linker. Applicant asserts that Sasaki does not disclose this architecture, and that in Sasaki, the azide groups are not conjugated to a J-aggregate. Rather, the azide groups are integral, covalently-bonded parts of the monomer's side chains - i.e., the azidohexyl chains are synthesized into the porphyrin monomer 6N3 before any self-assembly occurs, citing pp. 7844-7845 (Scheme 1, synthesis of 6N3 via bromide-to- azide substitution on the monomer itself). Applicant asserts that after the monomers self-assemble into a 2D supramolecular nanosheet, a BODIPY dye (BDP-DBCO) is reacted with the inherent azide groups of the constituent monomers.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that with regard to the assertion that in the claims, the MJ is formed first (by co-aggregation of a J-aggregate forming dye with a functionalized J-aggregate forming dye), and then a linker and functional moiety are conjugated to the MJ, it is respectfully submitted that the order in which components of MJ-E-D are formed does not distinguish over the product itself. With regard to the assertion that the azide groups are integral, covalently-bonded parts of the monomer's side chains - i.e., the azidohexyl chains are synthesized into the porphyrin monomer 6N3 before any self-assembly occurs, it is noted that the instant claims are broad and define the chemical structure of the compound. It is considered that the azide portion of the compound may be considered part of a linker and/or further it is noted that claims 17-20 require a J-aggregate forming dye functionalized with a linker. The BODIPY can be considered a functional moiety, i.e. fluorescent.
Applicant further argues that critically, in Sasaki: (1) the azide is not introduced to modify a pre-existing J-aggregate - it is an intrinsic part of the monomer before aggregation; and (2) the BODIPY attachment does not produce a discrete conjugate of the form "aggregate-linker-functional moiety."
As set forth above, it is respectfully submitted that the order in which components of MJ-E-D are formed does not distinguish over the product itself.
Applicant further argues that the specification further explains that the MJ is produced by co-aggregation of a J-aggregate forming dye (e.g., ICG) and a J-aggregate forming dye that has been functionalized (e.g., ICG-azide), in the presence of a salt. See Specification at 11 [0012], [0101]-[0102]. The MJ thus comprises a mixture of functionalized and unfunctionalized dye molecules that co-aggregate into a single aggregate structure. Applicant contends that Sasaki's 6N3NS nanosheet is something fundamentally different and that it is a two-dimensional supramolecular polymer formed from a single type of porphyrin monomer via "2D living supramolecular polymerization.", citing Sasaki at p. 7841.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that Sasaki specifically teaches that 6N3 forms short-slipping J-aggregate nanosheets on page 7841. The method by which the J-aggregates are formed does not distinguish over the product itself.
Applicant further argues that the product-by-process doctrine does not save the rejection. With regard to product-by-process limitations it is respectfully submitted that the disclosure of Sasaki meets the structural limitations of the instant claims, as set forth above. As such it is considered that the rejection of the product-by-process claims is proper.
With regard to the linker, Applicant further argues that the mere occurrence of a copper-free click chemistry reaction within an extended 2D supramolecular polymer does not satisfy claim 26 when the antecedent structural requirement of an MJ-E-D conjugate is not met. Moreover, in the claimed invention, E functions as a linker connecting MJ to D - i.e., it is a discrete molecular bridge (such as DBCO-PEG-Biotin or DBCO-PEG-Folate) tethering a functional moiety to the aggregate surface.
Applicant’s arguments have been fully considered. It is respectfully submitted that the Examiner’s response to the antecedent structural requirement is applied as above. The azide containing portion of the compound between 6N3NS, which forms J-aggregates as disclosed by Sasaki and which is joined via click chemistry BODIPY, a functional moiety is considered to be a part of a linker, as such the structural components of the claims have been addressed by Sasaki. The arguments have been considered but the rejection is maintained.
Claim(s) 14-17 and 23-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zou et al. (J. Am. Chem. Soc., 2017, 139, p. 1921−1927), as evidenced by Zhao et al. (CCS Chem., 2021, 3, 678–693).
Zou discloses that the self-assembling nature of porphyrins induces the formation of J-aggregates as substructures of the nanodots, and thus enables the fabrication of nanodots with totally inhibited fluorescence emission and singlet oxygen production, leading to a high light-to-heat conversion efficiency of the nanodots. The peptide moieties not only provide aqueous stability for the nanodots through hydrophilic interactions, but also provide a spatial barrier between porphyrin groups to inhibit the further growth of nanodots through the strong π-stacking interactions. Thermographic imaging reveals that the conversion of light to heat based on the nanodots is efficient in vitro and in vivo, enabling the nanodots to be applied for photothermal acoustic imaging and antitumor therapy. Antitumor therapy results show that these nanodots are highly biocompatible photothermal agents for tumor ablation, demonstrating the feasibility of using bioinspired nanostructures of self-assembling biomaterials for biomedical photoactive applications (page 1921).
Self-assembly of a peptide−porphyrin conjugate (TPP-G-FF) into photothermal peptide−porphyrin nanodots (PPP-NDs) is shown in Figure 1.
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C Corresponding structures show that the TPP moieties are apt to form J-aggregates, in which the distances between two TPP moieties are 3.6−4.2 Å, and the average energy due to the π-stacking is around −27 kcal mol−1 for each interaction pair, indicating strong hydrophobic effects. In addition, the FF chains are either stretched into the solvent (page 1922).
Accordingly development of photothermal nanodots by self assembling peptide−porphyrin conjugates as PA and PTT agents is shown. On account of the combinations of non-covalent interactions of peptides and porphyrins, these spherical PPP NDs possess tunable diameter, high aqueous stability, excellent stability against dilution and irradiation, and relatively high light-to-heat conversion efficiency of 54.2%. The impressive efficiency facilitates the application of PPP-NDs for PA imaging and PTT. Extensive in vivo evaluations of PPP-NDs demonstrate their high biocompatibility to mice, accumulation in tumors, and efficient inhibition of the tumors. This study shows that stable photothermal nanodots can be constructed through rational design of self-assembling building blocks of peptides and light-absorbing molecules.
This short peptide-tuned self-assembly strategy could be a powerful concept to construct efficient phototherapeutic nanomaterials together with various light-absorbing molecules, especially those possess near-infrared absorbance. More therapeutic effects, such as tumor targeting, can be integrated in the nanodots by tailoring the amino acid sequence of the peptide. Therefore, photothermal nanodots formed by self-assembly of small biomolecule combinations show flexibility, versatility, and adaptability for antitumor diagnosis and therapy. This will offer a new perspective in design of supramolecular therapeutic agents and may advance toward clinical translation and use of such biomaterials and nanomedicine (page 1925-6).
With regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Normally, only one reference should be used in making a rejection under 35 U.S.C. 102. However, a 35 U.S.C. 102 rejection over multiple references has been held to be proper when the extra references are cited to: (A) Prove the primary reference contains an "enabled disclosure;" (B) Explain the meaning of a term used in the primary reference; or (C) Show that a characteristic not disclosed in the reference is inherent. For example, "to serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill." Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749 (Fed. Cir. 1991). See MPEP 2131.01.
Zhao discloses that supramolecular assembly of organic dye compounds with J-aggregation leads to a red-shifted absorption spectrum that greatly facilitates the construction of near-infrared (NIR) materials (abstract). As a total consequence, the relative energy between the chromophore aggregates and monomers, that is, [EF (k) − ES1 ], crucially relies on the chromophore geometries. When JCoul is negative, the excitation energy of the aggregates is smaller than the monomers, resulting in a red-shifted absorption; the aggregates are slipped “head-to-tail” and are defined as J-aggregates (page 679).
Accordingly, in the instant case, Zhao is included to show that J-aggregate forming dyes, as disclosed by Zou, are necessarily capable of “head-to-tail” orientation.
Response to arguments
Applicant argues that as demonstrated above in Applicant's response to the Zheng rejection (Section A), the specification defines the "modified J-aggregate" as a self-assembled aggregate of dye molecules held together by non-covalent interactions (I [0007]), which is directly functionalized without the use of nanocarriers (II [0007], [0095]-[0096]), and which a structurally discrete aggregate component within the conjugate (IT [0096], [0177]; Example 1). That discussion is incorporated here by reference and will not be repeated. Zou does not disclose an MJ within this meaning. In Zou, the J-aggregation of TPP (tetraphenylporphyrin) moieties occurs only as a substructure within self-assembled peptide-porphyrin nanodots (PPP-NDs). The nanodots are formed from a pre-synthesized molecular conjugate (TPP-G-FF) - a porphyrin covalently bonded to a dipeptide (diphenylalanine, FF) through a glycine linker - that self-assembles into spherical nanodots through a combination of π-stacking, hydrophobic effects, and hydrophilic interactions of the peptide moieties. There is no discrete, standalone J-aggregate of dye molecules that exists as an independent particle.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the claims are not commensurate in scope with the arguments. A statement such that there still exists a critical need to assemble J-aggregates whose size can be easily tailored for imaging applications without using complicated synthesis methods or nanocarriers as in paragraph 0007 of the specification does not amount to a definition. The claims do not recite a discrete, standalone J-aggregate of dye molecules that exists as an independent particle as argued by Applicant. Further, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant further argues that Zou fails to disclose the conjugate formula MJ-E-D as recited in claim 14. Applicant asserts that the formula requires three discrete structural components: (i) a modified J-aggregate (MJ), (ii) a linker or bond (E), and (iii) a functional moiety (D), arranged such that E connects MJ to D. In Zou's system, the porphyrin (TPP) is covalently bonded to the peptide (FF) via a glycine residue at the molecular level before any self-assembly occurs. The resulting nanodot is a self-assembled structure of identical TPP-G-FF molecular units. Applicant argues that there is no step in which a pre-formed J-aggregate is connected via a linker to a functional moiety, there is no post-assembly conjugation event, and there is no "E" connecting an aggregate to a "D."
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that TPP forms a J aggregate in the nanodot, and is linked to a peptide (functional moiety) via a glycine linker, as such meets the structural limitations of the instant claims. With regard to the assertion that there is no step in which a pre-formed J-aggregate is connected via a linker to a functional moiety or post-assembly conjugation, it is respectfully submitted that the order in which components of MJ-E-D are formed does not distinguish over the product itself.
Applicant further argues that claims 16 and 17, which depend from claim 14, require that the MJ comprises a J-aggregate forming dye that has been functionalized.
Applicant’s arguments have been fully considered but are not found to be persuasive. The TPP has been functionalized, i.e. at least has been conjugated with a linker + peptide.
Applicant further argues that the product-by-process doctrine does not save the rejection. With regard to product-by-process limitations it is respectfully submitted that the disclosure of Sasaki meets the structural limitations of the instant claims, as set forth above. As such it is considered that the rejection of the product-by-process claims is proper.
Claim(s) 14-17, 23-25, 29 and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lettieri et al. (New J. Chem., 2012, 36, p. 1246–1254).
Lettieri discloses glucosylated steroid-porphyrins as new tools for nanotechnology applications. Specifically, the aggregation propensity of mono- and disubstituted porphyrin scaffolds was studied in DMSO–H2O (40/60, v/v), where J-type aggregates were detected by the broadening and bathochromic shift of the Soret absorption band (page 1246).
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J-aggregates are stated to be end-to-end in orientation, see page 1246.
With regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Response to arguments
Applicant argues that Lettieri does not describe a modified J-aggregate. Lettieri describes glucosylated steroid-modified porphyrins - i.e., monomeric compounds bearing glucosteroid substituents as integral parts of their molecular structure - that form J-type aggregates when dissolved in DMSO-H20 (40/60, v/v). Applicant asserts that Lettieri describes a molecule that forms J-aggregates. That is not the same as the claimed MJ conjugate of Formula MJ-E-D. Applicant contends that the Examiner appears to have equated "any compound that forms a J-aggregate" with the claimed "MJ conjugate," but these are fundamentally different concepts.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the porphyrin portion of the molecule corresponds to a functionalized dye that forms J-aggregates; a bond corresponds to E according to the instant claims, and a glucosylated steroid corresponds to a functional moiety according to the instant claims. It is respectfully submitted that the claims do not define where any specific structure that limits where a dye ends and a linker begins.
Applicant further argues that claims 16 and 17 require that the MJ comprises "a J-aggregate forming dye that has been functionalized." Applicant asserts that "functionalized" in the context of this specification means chemically modified with a reactive handle (e.g., an azide group) enabling post-assembly conjugation to a functional moiety. See paragraph [0010]; claims 18-19. Applicant contends that Lettieri's glucosylated steroid-porphyrins are not "functionalized" in this sense. The glucosteroid substituents are permanent, designed structural features of the monomer - they do not serve as reactive handles for subsequent conjugation to targeting moieties, drugs, or other functional groups. The Examiner has not explained how a pre-synthesized glucosylated steroid-porphyrin constitutes a "J-aggregate forming dye that has been functionalized" within the meaning of these claims. Applicant asserts that regarding claims 29 and 34, a drug, protein, etc. are not recited.
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted that the claims do not define where any specific structure that limits where a dye ends and a linker begins. The assertion that "functionalized" in the context of this specification means chemically modified with a reactive handle (e.g., an azide group) enabling post-assembly conjugation to a functional moiety is not commensurate in scope with the claims. It is further noted that a steroid is within the scope of a drug, as claimed, and as evidenced by instant claim 34.
Applicant further argues that the product-by-process doctrine does not save the rejection. With regard to product-by-process limitations it is respectfully submitted that the disclosure of Lettieri meets the structural limitations of the instant claims, as set forth above. As such it is considered that the rejection of the product-by-process claims is proper.
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.
Claim(s) 14-17, 21-25, 32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (US 2017/0319719) in view of Ito (US 2013/0209367) and Zhao et al. (CCS Chem., 2021, 3, 678–693).
Zheng teaches a nanovesicle having a bilayer comprising a saturated first phospholipid and no more than about 15 molar % of a second phospholipid covalently conjugated to a J-aggregate forming dye (paragraph 0006).
The nanoparticles are useful for fluorescence or photo-acoustic imaging or temperature monitoring.
In an aspect, there is provided a method of monitoring temperature at a target site comprising: providing the nanovesicle of any one of claims 1-20 at the target site, and monitoring a photoacoustic signal at the target site (paragraph 0009).
Preferably, the dye is selected from the group consisting of pseudoisocyanine, merocyanine, bis(2,4,6-trihydroxyphenyl)squaraine, Zn-chlorin, tetrtakis(4-sulfonatophenyl)-porphyrin, bacteriochlorin, antimony(III)-phthalocyanine, copper phthalocyanine and perylene bismide, Hypericin, subphtalocyanine, preferably bacteriochlorin. Further preferably, the second phospholipid covalently conjugated to the J-aggregate forming dye is bacteriochlorophyll-lipid (paragraph 0028).
In some embodiments, the dye is conjugated to the glycerol group on the second phospholipid by a carbon chain linker of 0 to 20 carbons (paragraph 0035).
Exemplary J-nanoparticles comprise Bchl-lipid, PEG2000-DPPE and host lipids, and photoacoustic imaging is performed (paragraph 0046-0054).
h regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)
Zheng does not specifically recite wherein the j-aggregate forming dye is ICG.
Ito teaches that ICG may contain J-aggregates, having the absorption maximum around 895 nm (paragraph 0047).
Nanoparticles enable the generation of the photoacoustic signal at both 790 nm (ICG monomer absorption) and 895 nm (the J-aggregates absorption). The photoacoustic imaging at multiple optical wavelengths can produce quantitative optical absorption reconstructions, which is effective in the improvement of accuracy of the nanoparticle detection in vivo (paragraph 0288).
Zhao teaches that supramolecular assembly of organic dye compounds with J-aggregation leads to a red-shifted absorption spectrum that greatly facilitates the construction of near-infrared (NIR) materials (abstract). As a total consequence, the relative energy between the chromophore aggregates and monomers, that is, [EF (k) − ES1 ], crucially relies on the chromophore geometries. When JCoul is negative, the excitation energy of the aggregates is smaller than the monomers, resulting in a red-shifted absorption; the aggregates are slipped “head-to-tail” and are defined as J-aggregates (page 679).
It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute ICG as a functionally equivalent dye which is capable of forming j-aggregates to those utilized by Zheng when the teaching of Zheng is taken in view of Ito. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known photoacoustic imaging dye which forms a j-aggregate for another, and the results of the substitution would have been predictable, that is provision of a nanovesicle comprising a phospholipid covalently conjugated to a J-aggregate forming dye. Zhao is included to show that J-aggregate forming dyes, as taught by Zheng, are necessarily capable of “head-to-tail” orientation.
Response to arguments
Applicant argues that as set forth in detail in the response to the § 102(a)(1) rejection over Zheng above, Zheng does not disclose the claimed "modified J-aggregate" (MJ) or the conjugate architecture MJ-E-D.
The Examiner’s response to Applicant’s arguments regarding Zheng is incorporated as above.
Applicant argues that Ito does not cure Zheng's deficiencies. Applicant asserts that neither Zheng nor Ito - alone or in combination - discloses the claimed MJ conjugate architecture (MJ-E-D). Applicant contends that (a) Substituting ICG for bacteriochlorin in Zheng's system would yield a lipid nanovesicle with ICG covalently conjugated to a phospholipid - not an MJ conjugate of formula MJ-E-D. The identity of the dye does not change the fundamental architecture of Zheng's lipid-based nanocarrier system. (b) Ito itself discloses ICG-containing nanoparticles for photoacoustic imaging (Ito, paragraph [0288]). Ito's nanoparticles are similarly lipid-based or polymer-based constructs - they are not self-assembled dye aggregates that are subsequently linked to a functional moiety via a linker. (c) Neither reference teaches, suggests, or provides motivation to form a self-assembled J- aggregate of dye molecules, modify it with reactive functional groups (e.g., azide), and then conjugate a functional moiety to the aggregate via a linker. Claims 16-17 require that the MJ comprises "a J-aggregate forming dye that has been functionalized." As discussed above, "functionalized" means modified with a reactive handle (e.g., an azide group) enabling post-assembly conjugation.
Applicant asserts that neither Zheng nor Ito teaches, suggests, or motivates a person of ordinary skill in the art to: Form a self-assembled J-aggregate from dye molecules (rather than incorporating dye into a lipid bilayer); Modify the J-aggregate by incorporating a functionalized dye bearing a reactive handle; Conjugate the resulting modified J-aggregate to a functional moiety via a linker.
Applicant’s arguments have been fully considered. It is respectfully submitted that Applicant’s argument that the dyes are not self-assembled dye aggregates that are subsequently linked to a functional moiety via a linker are not persuasive, as set forth above. It is respectfully submitted that the references address the structural elements of the claims. The order of addition of a linker to a J-aggregate forming dye, such as conjugation of a linker-functional moiety to a preformed or aggregation of a dye linked to a functional moiety does not distinguish over the structural elements of the claimed components and that of the prior art. With regard to the assertion that "functionalized" means modified with a reactive handle (e.g., an azide group) enabling post-assembly conjugation, limitations from the specification are not read into the claims, as set forth above. In the instant case, each of Zheng and Ito are directed to J-aggregate forming dyes. One of ordinary skill in the art could have readily substituted ICG, as taught by Ito, for another J-aggregate forming dyes for linkage to phospholipid, as taught by Zheng. The arguments have been fully considered but the rejection is maintained.
Claim(s) 14-17, 21-25, 35 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (US 2017/0319719) in view of Wang et al. (J. Mater. Chem. B, 2015, 3, 3297-3305) and Zhao et al. (CCS Chem., 2021, 3, 678–693).
Zheng teaches a nanovesicle having a bilayer comprising a saturated first phospholipid and no more than about 15 molar % of a second phospholipid covalently conjugated to a J-aggregate forming dye (paragraph 0006).
The nanoparticles are useful for fluorescence or photo-acoustic imaging or temperature monitoring.
In an aspect, there is provided a method of monitoring temperature at a target site comprising: providing the nanovesicle of any one of claims 1-20 at the target site, and monitoring a photoacoustic signal at the target site (paragraph 0009).
Preferably, the dye is selected from the group consisting of pseudoisocyanine, merocyanine, bis(2,4,6-trihydroxyphenyl)squaraine, Zn-chlorin, tetrtakis(4-sulfonatophenyl)-porphyrin, bacteriochlorin, antimony(III)-phthalocyanine, copper phthalocyanine and perylene bismide, Hypericin, subphtalocyanine, preferably bacteriochlorin. Further preferably, the second phospholipid covalently conjugated to the J-aggregate forming dye is bacteriochlorophyll-lipid (paragraph 0028).
In some embodiments, the dye is conjugated to the glycerol group on the second phospholipid by a carbon chain linker of 0 to 20 carbons (paragraph 0035).
Exemplary J-nanoparticles comprise Bchl-lipid, PEG2000-DPPE and host lipids, and photoacoustic imaging is performed (paragraph 0046-0054).
J-aggregate forming nanoparticle (JNP) are capable of directly responding to environmental changes in temperature with potential application in focal thermal therapy response monitoring (paragraph 0025).
Zheng does not specifically recite wherein doxorubicin is conjugated through a linker to a j-aggregate.
Wang teaches that ideal drug delivery systems should have prolonged circulation in blood, high accumulation in tumors with fast cellular uptake and burst drug release in cancer cells. Herein, a pH-sensitive small-molecule phospholipid prodrug based on phosphorylcholine (PC) was designed to overcome these challenges. The prodrug was synthesized by conjugating doxorubicin (DOX) to 11-mercaptoundecyl phosphorylcholine via an acid-labile hydrazone linker (UnPC-hyd-DOX). This phospholipid prodrug can self-assemble into core–shell micelles with exact and very high drug loading content (56.2%). Interest ingly, the PC prodrug micelles can strongly minimize nonspecific phagocytosis by macrophages. They exhibited better ability to be internalized by cancer cells than that of the PEG prodrug micelles, which indicated that the PC shell facilitated cancer cell internalization (page 3297).
Zhao discloses that supramolecular assembly of organic dye compounds with J-aggregation leads to a red-shifted absorption spectrum that greatly facilitates the construction of near-infrared (NIR) materials (abstract). As a total consequence, the relative energy between the chromophore aggregates and monomers, tha is, [EF (k) − ES1 ], crucially relies on the chromophore geometries. When JCoul is negative, the excitation energy of the aggregates is smaller than the monomers, resulting in a red-shifted absorption; the aggregates are slipped “head-to-tail” and are defined as J-aggregates (page 679).
It would have been further obvious to provide a therapeutic agent such as doxorubicin conjugated to phospholipid when the teaching of Zheng is taken in view of Wang. One would have been motivated to do so in order to delivery a therapeutic agent because Zheng teaches that the J-aggregate forming nanoparticles (JNP) are suitable for monitoring therapeutic response. One would have had a reasonable expectation of success in doing so because Wang shows that doxorubicin conjugated to phospholipids
an drug delivery systems should have prolonged circulation in blood, high accumulation in tumors with fast cellular uptake and burst drug release in cancer cells.
With regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Zhao is included to show that J-aggregate forming dyes, as taught by Zheng, are necessarily capable of “head-to-tail” orientation.
Response to arguments
Applicant argues that Zheng does not disclose the fundamental structural architecture of claim 14. The § 103 analysis relies on Zheng as disclosing the baseline MJ- E-D conjugate, to which Wang's doxorubicin-phospholipid prodrug is allegedly combined. However, Zheng does not disclose an MJ or an MJ-E-D conjugate in the first place.
The Examiner’s response to Applicant’s arguments directed to Zheng is applied as above.
Applicant further argues that Wang does not supply the missing elements of claim 14. Applicant asserts that Wang teaches a phospholipid-drug conjugate that self-assembles into a micelle. This is a fundamentally different architecture from a pre-formed J-aggregate to which a functional moiety is subsequently attached via a linker. Applicant further argues that the Examiner’s stated motivation would lead skilled artisan to add a doxorubicin-phospholipid to Zheng's lipid nanovesicle bilayer - it would not lead to the claimed invention, which is a self-assembled dye aggregate (not a lipid nanovesicle) conjugated via a linker to a functional moiety. The claimed conjugate solves a different problem (direct functionalization of dye aggregates without nanocarrier encapsulation) using a different approach (co- aggregation of functionalized and unfunctionalized dyes, followed by click chemistry conjugation to functional moieties).
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted that the rejection is based upon the combined teaching of Zheng and Wang. With regard to the assertion that Wang’s teaching is fundamentally different architecture from a pre-formed J-aggregate to which a functional moiety is subsequently attached via a linker, it is noted that the combined teachings of references address the structural elements of the claims. The order of addition of a linker to a J-aggregate forming dye, such as conjugation of a linker-functional moiety to a preformed or aggregation of a dye linked to a functional moiety does not distinguish over the structural elements of the claimed components and that of the prior art.
Claim(s) 14-29 and 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (US 2017/0319719) in view of in view of Ito (US 2013/0209367) and Zhao et al. (CCS Chem., 2021, 3, 678–693), in further view of Changalvaie et al. (ACS Appl. Mater. Interfaces, 2019, 11, p. 46437−46450).
The rejection over Zheng in view of Ito and Zhao is applied as above.
With regard to linking chemistry, Zheng and Ito do not specifically recite click chemistry including azide and DBCO-PEG-amine containing linkers to link an antibody.
Changalvaie teaches clinical translation of photoacoustic imaging (PAI) has been limited by the lack of near-infrared (NIR) contrast agents with low toxicity required for regulatory approval. J aggregates of indocyanine green (ICG) with strong NIR absorbance were encapsulated at high loadings within small 77 nm polymersomes (nanocapsules) composed of poly(lactide-co-glycolide-b-poly(ethylene gly col)) (PLGA-b-PEG) bilayers, thus enabling PAI of of breast and ovarian cancer cells with high specificity and a sensitivity at the level of ∼100 total cells.
The objective of this study was to encapsulate ICGJ with very limited dissociation into PLGA-b-PEG (90K:10K) Ps with grafted monoclonal antibodies (mAbs) to target cancer cells for high contrast NIR PAI (page 46438).
Polymersomes showing encapsulated ICGJ@PEI NPs surrounded by the PEG−PLGA bilayer. The antibodies are bonded to azide end groups on the PEG segments via click chemistry in Figure 3.
Anti-EGFR antibodies are linked via a bifunctional DBCO-PEG-aminooxy linker (page 46440).
It would have been obvious to one of ordinary skill in the art at the time of the invention to incorporate an antibody as a targeting ligand on the vesicles taught by Zheng and Ito when the teachings of Zheng and Ito are taken in view of Changalvaie. One would have been motivated to do so because Zheng is directed to j-aggregate nanoparticles useful for fluorescence or photo-acoustic imaging, and Changalvaie teaches that providing antibody linked via click chemistry, including azide and DBCO-PEG-amine containing linker allows for site-specific imaging with high specificity.
With regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Response to arguments
Applicant argues that Zheng does not disclose the claimed MJ-E-D conjugate architecture. Applicant asserts that Changalvaie does not supply the missing MJ-E-D architecture. Applicant contends that in Changalvaie, the ICG J-aggregates are encapsulated inside a polymeric nanocarrier (polymersome), and the antibodies are conjugated to the polymersome shell - not to the J-aggregate itself. Applicant notes that Changalvaie's architecture is: [J-aggregate] encapsulated inside [polymersome]-[inker]-[antibody] The claimed architecture is: [modified J-aggregate]-[linker]-[functional moiety].
Applicant’s arguments have been fully considered but are not found to be persuasive. The Examiner’s response to the arguments directed to Zheng and Ito are applied as above. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Chanalvaie is included to address known methods by which to link an antibody to a polymer which allows for site-specific imaging with high specificity.
Applicant further argues that the proposed combination does not arrive at the claimed invention combining Zheng (lipid nanovesicle with dye-conjugated phospholipid), Ito (ICG forms J- aggregates), and Changalvaie (ICG J-aggregates encapsulated in polymersomes with antibodies on the shell) would yield, at most, a nanocarrier containing J-aggregates with antibodies on the carrier surface. This is still a nanocarrier-based system - not the claimed MJ-E-D conjugate in which a functional moiety is directly linked to a modified J-aggregate without an intervening nanocarrier. Applicant argues that the motivation does not lead to the claimed invention. Applicant further argues that in Changalvaie, the azide groups are on the PEG segments of the polymersome shell, and click chemistry is performed on the nanocarrier - not on the J-aggregate itself.
Applicant’s arguments have been fully considered, but are not persuasive. It is respectfully submitted that the MJ-E-D structure was addressed by Zheng, as set forth above. Provision of an alternative linking chemistry would have been an obvious modification to one of ordinary skill in the art, and one would have found motivation to link an antibody to a PAI agent, because Changalvaie teaches that doing so allows for site specific PAI. With regard to the argument the click chemistry is performed on the nanocarrier, it is respectfully submitted that the rejection is based on the combined teachings of the references, and further the claims do not recite the identity and/or relative position of the dye and linker. With regard to product-by-process limitations it is respectfully submitted that the disclosure of Sasaki meets the structural limitations of the instant claims, as set forth above. As such it is considered that the rejection of the product-by-process claims is proper.
Claim(s) 14-17, 21-25, 28, 29 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Whitten et al. (US 2008/0044805) in view of Zhao et al. (CCS Chem., 2021, 3, 678–693).
Whitten teaches that certain cyanine dyes form molecular aggregates that are either J-type or H-type depending upon their chemical structure and media. H aggregates have a blue-shifted absorption band, relative to the absorption wavelength of the monomeric dye. J-aggregates, on the other hand, have a narrower, red-shifted absorption band, compared to the monomer and also show a sharp, intense fluorescence emission compared to the monomer or other aggregates. The sharp emission spectra of J-aggregated cyanines and the structural diversity of the cyanines have made them attractive candidates for fluorescence-based sensing applications. However, although J-aggregation has been observed in a variety of environments, it is still unclear which factors tip the balance in favor of J-aggregation for structurally similar families of cyanines. For example, it has been found that while certain cyanines form J-aggregates when adsorbed onto clay nanoparticles, seemingly structurally similar cyanines may exhibit H-aggregation or dimerization when bound to the same type of clay nanoparticles. Additionally, in many cases the potential utility of the cyanine dyes is impaired by the low quantum efficiency for most J-aggregate fluorescence (paragraph 0008).
According to various embodiments of the present invention, certain cyanine dyes and related chromophores, including but not limited to, cyanine dyes of Formula I, can form stable, tight complexes with chiral polymeric molecules in aqueous solutions resulting in the formation of intensely fluorescent J-aggregates. This molecular aggregation occurs via cooperative self assembly in which both the dye and the polymer undergo conformational changes to adopt a supramolecular helical structure. In some embodiments, a charged cyanine dye may associate with an uncharged or oppositely charge biopolymer. It may be desirable for chirality to be taken into account, for example, when detection methods such as induced circular dichroism are used (paragraph 0040).
Assays of the present invention may be conducted by any means applicable, for example using a solid phase support. In some embodiments, one or more of the reagents may be pre-loaded on a solid phase support. For example, the solid phase support may contain cyanine dye, biopolymers, enzymes, cyanine dye: biopolymer complexes, or any combination thereof. In another embodiment, the solid phase support may contain one or more capture zones capable of binding cyanine dye, biopolymers, enzymes, biopolymer fragments, cyanine dye: biopolymers, analytes, or any combination thereof. Such capture zones may or may not contain additional labels capable of emitting a signal when a reaction is completed. In some embodiments, capture zones may include, but are not limited to, one or more reaction zones containing one or more bound antibody-enzyme conjugates or other recognition molecules bound to an enzyme that disrupts biopolymer:cyanine dye complexes, biopolymer:dye complexes, molecules specific for the biopolymer under investigation; one or more recognition zone containing molecules specific for biopolymers under investigation; one or more detection zones containing biopolymer:cyanine dye complexes; one or more test zones containing antibodies or other affinity ligands for intact biopolymer and/or biopolymer fragments, including but not limited to DNA strands, additional biopolymers capable of trapping cyanine dye; one or more control zones containing molecules capable of forming chem-bio helices with cyanine dye and/or producing the spectral changes associated with J-aggregate formation such as, but not limited to, clay nanoparticles, DNA or RNA duplexes, or biopolymers such as, but not limited to, linear polysaccharides such as cellulose, including carboxymethylamylose (CMA) and carboxymethylcellulose (CMC), and glycosaminoglycans; and proteins or structures composed of proteins such as albumin, Bacillus collagen-like antigen, cell membranes, phospholipids bilayers, liposomes, reverse micelles and gelatin, or any other appropriate molecules; as well as any other applicable capture zones. Antibodies, affinity ligands, biopolymers, cyanine dye or recognition molecules in the capture zones may be adsorbed, covalently linked, conjugated via ligand protein association or other non-covalent linkage, trapped or otherwise attached to or associated with the solid phase support. It is known to functionalize cyanine, accordingly it should be possible to biotinylate, cyanine. Biotinylated cyanine may be immobilized via streptavidin-biotin interactions. For example, in some embodiments, the molecules may be isolated in a capture zone using a size permeation filter. In another embodiment, an antibody may be adsorbed to the solid phase supports. In other embodiments, the antibodies, antibody-enzyme conjugates, affinity ligands, recognition molecules, or recognition molecule-enzyme conjugates may be mobile. Signals including, but not limited to, shifts in J-aggregate emissions, may be measured at some or all of the capture zones (paragraph 0056).
Whitten does not specifically recite wherein the dye geometry is in a head-to tail orientation.
Zhao discloses that supramolecular assembly of organic dye compounds with J-aggregation leads to a red-shifted absorption spectrum that greatly facilitates the construction of near-infrared (NIR) materials (abstract). As a total consequence, the relative energy between the chromophore aggregates and monomers, that is, [EF (k) − ES1 ], crucially relies on the chromophore geometries. When JCoul is negative, the excitation energy of the aggregates is smaller than the monomers, resulting in a red-shifted absorption; the aggregates are slipped “head-to-tail” and are defined as J-aggregates (page 679).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide biotin linked to a j-aggregate forming cyanine dye in view of Whitten. One would have been motivated to do so, with a reasonable expectation of success, because Whitten teaches that it is known to functionalize cyanine and should be possible to biotinylate cyanine. Whitten teaches that doing so allows for biotinylated cyanine to be immobilized via streptavidin-biotin interactions such as isolation in a capture zone using a size permeation filter.
With regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Zhao is included to show that J-aggregate forming dyes, as taught by Whitten, are necessarily capable of “head-to-tail” orientation.
Response to arguments
Applicant argues that Whitten discloses cyanine dyes that form J-aggregates via cooperative self-assembly with chiral biopolymers (e.g., polysaccharides, DNA) in aqueous solution, citing Whitten at paragraph [0040]. Applicant asserts that these are dye: biopolymer complexes - supramolecular helical structures in which a charged cyanine dye associates with a biopolymer - for use in fluorescence-based assay applications. Whitten's paragraph [0056] states in relevant part that "it is known to functionalize cyanine, accordingly it should be possible to biotinylate cyanine" and that "[b]iotinylated cyanine may be immobilized via streptavidin-biotin interactions." Appllicant contends that the Examiner relies on this passage to construct the claimed MJ-E-D conjugate, but that Whitten does not disclose the claimed subject matter for at least three independent reasons: 1. Whitten's J-Aggregates are dye: biopolymer complexes - not modified J-Aggregates (MJ) The claimed MJ is a J-aggregate of dye molecules containing stable head-tail arrangements of dye molecules held together by non-covalent interactions - i.e., a self-assembled aggregate of dye held together by non-covalent interactions between dye molecules. See Specification at paragraph [0007]. In Whitten, the J-aggregation is not a standalone dye aggregate. Rather, it is a dye: biopolymer complex - the cyanine dye and a biopolymer "undergo conformational changes to adopt a supramolecular helical structure" (paragraph [0040]). The biopolymer is an essential structural component of the aggregate.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the arguments are not commensurate in scope with the claims. The claims do preclude the presence of additional components in addition to MJ-E-D. Further, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant further argues that Whitten does not disclose biotinylating of a J-Aggregate - only speculative biotinylating of monomeric dye. Applicant asserts that Whitten does not teach or suggest: (a) Forming a J-aggregate from that biotinylated cyanine (with or without unfunctionalized dye); (b) Using the biotin as a linker to connect a functional moiety to a pre-formed J-aggregate; or (c) Creating a free-standing MJ-E-D conjugate particle.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that with regard to the assertion that there is no pre-formed J-aggregate to which a functional moiety is subsequently attached via a linker, it is noted that the order in which components of MJ-E-D are formed does not distinguish over the product itself.
If one were to biotinylate a cyanine monomer and then form a J-aggregate from it, the result would be an aggregate in which every monomer unit bears a biotin substituent. This is not the architecture MJ-E-D. In the claimed conjugate, D is a functional moiety attached to the aggregate MJ through a linker E - i.e., one or more discrete functional moieties tethered to the aggregate surface. In the hypothetical Whitten construct, biotin would be an integral part of each dye monomer throughout the aggregate - there is no discrete "linker" (E) connecting an "aggregate" (MJ) to a "functional moiety" (D). The construct would be more accurately described as an aggregate of biotinylated monomers - not MJ-E-D.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the dyes aggregate in J-aggregate form. The presence of any number of linker-functional moieties are not excluded by the instant claims. The chemical structure of the dye, linker or functional moieties are not defined by the claims with a degree of specificity to exclude “additional” linker-functional group moieties or that the functional moieties are tethered to the aggregate “surface”, as asserted by Applicalnt.
Applicant argues that claims 16-17 require that MJ comprises "a J-aggregate forming dye that has been functionalized." In the context of the specification, this means a dye bearing a reactive handle (e.g., azide group) that enables post-assembly conjugation to a functional moiety. See paragraph [0010]; claims 18-19. Whitten's hypothetical biotinylated cyanine is not "functionalized" in this sense - biotin is not a reactive handle for post-assembly conjugation, and Whitten does not teach incorporating a functionalized dye into a J-aggregate alongside unfunctionalized dye. Applicant further argues that the product implied by claims 23-25 - a co-aggregate of functionalized and unfunctionalized dye molecules formed in the presence of a salt - is not disclosed or suggested by Whitten. Whitten's J-aggregates form via cooperative self-assembly with biopolymers, not by salt-induced co-aggregation of mixed dye species.
Applicant’s arguments have been fully considered but are not persuasive. in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, biotinization is considered to be modification of a cyanine dye, i.e. functionalization through a bond. The claims are not limited to an azide handle. With regard to product-by-process limitations it is respectfully submitted that the disclosure of Sasaki meets the structural limitations of the instant claims, as set forth above. As such it is considered that the rejection of the product-by-process claims is proper.
Claim(s) 14-17, 21-25, 28 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over McBranch et al. (US 2002/0177136) in view of Zhao et al. (CCS Chem., 2021, 3, 678–693).
McBranch teaches a novel chemical moiety formed of a polymer (P), a first tethering element (T), a ligand (L), a second tethering element (T'), and a quencher (Q). It is another object of the present invention to provide a method of detecting nucleic acids in a target sample using the novel PTLT'Q molecule of the present invention (paragraph 0010-11).
The key scientific basis for the polymer QTL approach is the amplification of quenching of fluorescence that may be obtained with certain charged polymers, including, but not limited to, conjugated polymers and dye-pendant polyelectrolytes in which the chromophores are collected by non-covalent interactions (e.g., J-aggregation), and small molecule quenchers. The fluorescent polymers provide amplification over conventional molecular fluorophores both by virtue of their light-harvesting properties (collective excitation) and their sensitivity to superquenching (i.e., one quencher may extinguish luminescence from an entire polymer chain) (paragraph 0023).
Fluorescent polymer superquenching has been adapted to biosensing applications through the use of "QTL" bioconjugates. (2-7). QTL bioconjugates contain a small molecule electron transfer or energy transfer quencher (Q), linked through a tether (T) to a ligand (L) for a specific bioagent (paragraph 0024).
Suitable examples of ligands that can be used in "QTL" methods include chemical ligands, hormones, antibodies, antibody fragments, oligonucleotides, antigens, polypeptides, glycolipids, proteins, protein fragments, enzymes, peptide nucleic acids (PNAs), and polysaccharides. Examples of suitable tethers include, without limitation, single bonds, single divalent atoms, divalent chemical moieties of up to approximately 10 carbon atoms in length, multivalent chemical moieties, polyethylene, polyethylene oxides, polyamides, non-polymeric organic structures of at least about 7-20 carbon atoms, and related materials. Suitable quenchers include methyl viologen, quinones, metal complexes, fluorescent and nonfluorescent dyes, and energy accepting, electron accepting, and electron donating moieties. However, these examples of the ligand, tethering elements, and quenchers are not to be construed as limiting, as other suitable examples would be easily determined by one of skill in the art (paragraph 0025).
Examples of the polymer for use in the PTLT'Q molecule include, but are not limited to, fluorescent polymers (including conjugated polymers), conjugated polyelectrolytes and dye pendant polymers (including polyelectrolytes). Suitable examples of the fluorescent polymer are conjugated polymers or oligomers including poly phenylene vinylene derivatives, poly (phenyleneethynylene) derivatives, polyphenylene derivatives, polythiophene derivatives, polyfluorene derivatives, neutral, anionic, and cationic conjugated polymers. The dye-pendant polymers can include those which interact through J-aggregation and consequently have very narrow absorption and emission spectra (paragraph 0033).
The J-aggregating dye polyelectrolytes offer very attractive possibilities for synthesis of a suite of molecules for multiplexing due to the narrow spectral band of emission in these polymer. Dye polymers that have an ionic fluorescent dye chromophore on each repeat unit on a non-conjugated polymer have previously been shown to exhibit strong J-aggregate absorption and fluorescence. (18-20). Suitable examples of fluorescent dyes for use in the present invention include symmetrical cyanine dye chromophores, unsymmetrical cyanine chromophores, merocyanine dyes, positively charged dye chromophores, negatively charged dye chromophores, and neutral dye chromophores (paragraph 0035).
McBranch does not specifically recite wherein the dye geometry is in a head-to tail orientation.
Zhao discloses that supramolecular assembly of organic dye compounds with J-aggregation leads to a red-shifted absorption spectrum that greatly facilitates the construction of near-infrared (NIR) materials (abstract). As a total consequence, the relative energy between the chromophore aggregates and monomers, that is, [EF (k) − ES1 ], crucially relies on the chromophore geometries. When JCoul is negative, the excitation energy of the aggregates is smaller than the monomers, resulting in a red-shifted absorption; the aggregates are slipped “head-to-tail” and are defined as J-aggregates (page 679).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide an antibody, protein or oligonucleotide as a ligand on a j-aggregated dye polyelectrolyte in view of McBranch. One would have been motivated to do so, with a reasonable expectation of success, because McBranch teaches antibody, protein, oligonucleotide to be one of a few suitable examples of ligands which are linked to PTLT'Q molecules for use as Polymer-Tether-Ligand-Tether-Quencher (PTLT'Q) system provides for effective sensing of nucleic acids by observing fluorescence changes.
With regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Zhao is included to show that J-aggregate forming dyes, as taught by McBranch, are necessarily capable of “head-to-tail” orientation.
Response to arguments
Applicant argues that McBranch does not disclose or suggest an MJ-E-D conjugate. Applicant asserts that McBranch discloses a Polymer-Tether-Ligand-Tether'-Quencher (PTLT'Q) molecule for nucleic acid detection via fluorescence superquenching. Applicant notes that McBranch notes that suitable fluorescent polymers include "dye-pendant polymers" that "interact through J-aggregation" (paragraph [0033]) and that "[d]ye polymers that have an ionic fluorescent dye chromophore on each repeat unit on a non-conjugated polymer have previously been shown to exhibit strong J-aggregate absorption and fluorescence" (paragraph [0035]). The Examiner appears to map this system onto claim 14 by treating the J-aggregating dye polyelectrolyte as "MJ" and the tether-ligand (e.g., antibody) as "E-D." Applicant argues that a covalent polymer with pendant dyes that happen to J-aggregate is not a "modified J-aggregate" - it is a polymer.
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted that the Specification describes a modified J-aggregate in paragraph 0098: In some embodiments, the MJ comprises a J-aggregate forming dye that has been functionalized. In some embodiments, the MJ comprises a J-aggregate forming dye and a J-aggregate forming dye that has been functionalized.
In the instant case, it is considered that McBranch describes a J-aggregate forming dye that is conjugated to a polymer as a J-aggregate forming dye that has been functionalized, thus the description in McBranch is consistent with the instant claims.
Applicant further argues that in McBranch's system, the polymer (P) and the QTL bioconjugate are separate molecules that interact non-covalently in a biosensing assay. The ligand (L) - e.g., an antibody or oligonucleotide - is part of the QTL bioconjugate and is connected to a quencher (Q), not to the polymer (P), citing paragraphs [0024]-[0025]. Applicant asserts that the fluorescent polymer is not conjugated to the ligand; rather, the ligand- quencher conjugate associates with the polymer to produce a fluorescence change upon analyte binding. Applicant contends this is not MJ-E-D and that in the claimed conjugate, D (the functional moiety) is covalently connected through E (linker) to the MJ (modified J-aggregate) as a single molecular entity. Applicant asserts that in McBranch, the polymer and the ligand-bearing quencher are separate, non-covalently interacting species in a multi- component assay system. Applicant further argues that McBranch does not teach or suggest attaching an antibody, protein, or other functional moiety directly to a J-aggregate via a linker to form a conjugate particle.
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted that in McBranch, the PTLT’Q components are indeed a single molecular entity. See e.g. Figure 6, shown below.
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In the instant case, the claims are quite broad, such that the identity of the MJ, E and D are not defined by chemical structure. As such, given the broadest reasonable interpretation, a functional moiety linked to a polymer/J-aggregate at any position on the polymer (i.e. modified) J-aggregate, as shown by McBranch, is encompassed by the instant claims. With regard to the argument that McBranch does not teach or suggest attaching an antibody, protein, or other functional moiety directly to a J-aggregate via a linker to form a conjugate particle, it is respectfully submitted that the linker or position of the linker is not specified due to the breadth of the instant claims. As such, the position/identity of the linker as taught by Branch on the polymer, which is part of a J-aggregate which has been modified by a polymer, is encompassed by the instant claims.
Applicant further argues that claims 16-17 require that the MJ comprises "a J-aggregate forming dye that has been functionalized." As discussed above, "functionalized" means modified with a reactive handle (e.g., an azide group) enabling post-assembly conjugation. Applicant further regarding claims 23-25 the structure implied bears no resemblance to McBride’s PTLT’Q assemblies.
With regard to the arguments directed the functionalization of an aggregate forming dye, it is respectfully submitted that the dye has been functionalized, at least by polymer and tether, as set forth above. With regard to product-by-process limitations it is respectfully submitted that the disclosure of Sasaki meets the structural limitations of the instant claims, as set forth above. As such it is considered that the rejection of the product-by-process claims is proper.
Claim(s) 14-17, 23-25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Zou et al. (J. Am. Chem. Soc., 2017, 139, p. 1921−1927) in view of Bradbury et al. (US 2013/0039848) and Zhao et al. (CCS Chem., 2021, 3, 678–693).
Zou teaches that the self-assembling nature of porphyrins induces the formation of J-aggregates as substructures of the nanodots, and thus enables the fabrication of nanodots with totally inhibited fluorescence emission and singlet oxygen production, leading to a high light-to-heat conversion efficiency of the nanodots. The peptide moieties not only provide aqueous stability for the nanodots through hydrophilic interactions, but also provide a spatial barrier between porphyrin groups to inhibit the further growth of nanodots through the strong π-stacking interactions. Thermographic imaging reveals that the conversion of light to heat based on the nanodots is efficient in vitro and in vivo, enabling the nanodots to be applied for photothermal acoustic imaging and antitumor therapy. Antitumor therapy results show that these nanodots are highly biocompatible photothermal agents for tumor ablation, demonstrating the feasibility of using bioinspired nanostructures of self-assembling biomaterials for biomedical photoactive applications (page 1921).
Self-assembly of a peptide−porphyrin conjugate (TPP-G-FF) into photothermal peptide−porphyrin nanodots (PPP-NDs) is shown in Figure 1.
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C Corresponding structures show that the TPP moieties are apt to form J-aggregates, in which the distances between two TPP moieties are 3.6−4.2 Å, and the average energy due to the π-stacking is around −27 kcal mol−1 for each interaction pair, indicating strong hydrophobic effects. In addition, the FF chains are either stretched into the solvent (page 1922).
Accordingly development of photothermal nanodots by self assembling peptide−porphyrin conjugates as PA and PTT agents is shown. On account of the combinations of non-covalent interactions of peptides and porphyrins, these spherical PPP NDs possess tunable diameter, high aqueous stability, excellent stability against dilution and irradiation, and relatively high light-to-heat conversion efficiency of 54.2%. The impressive efficiency facilitates the application of PPP-NDs for PA imaging and PTT. Extensive in vivo evaluations of PPP-NDs demonstrate their high biocompatibility to mice, accumulation in tumors, and efficient inhibition of the tumors. This study shows that stable photothermal nanodots can be constructed through rational design of self-assembling building blocks of peptides and light-absorbing molecules.
This short peptide-tuned self-assembly strategy could be a powerful concept to construct efficient phototherapeutic nanomaterials together with various light-absorbing molecules, especially those possess near-infrared absorbance. More therapeutic effects, such as tumor targeting, can be integrated in the nanodots by tailoring the amino acid sequence of the peptide. Therefore, photothermal nanodots formed by self-assembly of small biomolecule combinations show flexibility, versatility, and adaptability for antitumor diagnosis and therapy. This will offer a new perspective in design of supramolecular therapeutic agents and may advance toward clinical translation and use of such biomaterials and nanomedicine (page 1925-6).
Zou does not specifically teach wherein the peptide comprises RGD.
Bradbury teaches fluorescent silica-based nanoparticle that allows for precise detection, characterization, monitoring and treatment of a disease such as cancer. The nanoparticle has a fluorescent compound positioned within the nanoparticle. The nanoparticle may further be conjugated to a ligand capable of binding to a cellular component associated with the specific cell type, such as a tumor marker (abstract).
The ligand may be capable of binding to at least one cellular component, such as a tumor marker. The number of ligands attached to the nanoparticle may also range from about 1 to about 10. Examples of the ligand include peptide, protein, biopolymer, synthetic polymer, antigen, antibody, microorganism, virus, receptor, hapten, enzyme, hormone, chemical compound, pathogen, toxin, surface modifier, or combinations thereof. Peptides such as tripeptide RGD, cyclic peptide cRGD, octreotate, EPPT1 and peptide analogs of alpha-MSH are encompassed by the present invention. Any linear, cyclic or branched peptide containing the RGD sequence is within the scope of the present invention (paragraph 0009).
Zhao discloses that supramolecular assembly of organic dye compounds with J-aggregation leads to a red-shifted absorption spectrum that greatly facilitates the construction of near-infrared (NIR) materials (abstract). As a total consequence, the relative energy between the chromophore aggregates and monomers, that is, [EF (k) − ES1 ], crucially relies on the chromophore geometries. When JCoul is negative, the excitation energy of the aggregates is smaller than the monomers, resulting in a red-shifted absorption; the aggregates are slipped “head-to-tail” and are defined as J-aggregates (page 679).
It would have been obvious to one of ordinary skill in the art at the time of the invention to couple an RGD peptide as the peptide which is coupled to a j-aggregate forming dye as taught by when the teaching of Zou is taken in view of Bradbury. One would have been motivated to do so, with a reasonable expectation of success, because Zou teaches that tumor targeting, can be integrated in the nanodots by tailoring the amino acid sequence of the peptide, and Bradbury teaches that RGD is a tumor targeting sequence that can be coupled to nanoparticles.
With regard to claims 23-25, see MPEP 2123. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Zhao is included to show that J-aggregate forming dyes, as taught by Zou, are necessarily capable of “head-to-tail” orientation.
Response to arguments
Applicant argues that for the reasons argued in detail above with respect to the §102 rejection over Zou, the primary reference does not disclose the claimed MJ-E-D conjugate architecture.
The Examiner’s response to Applicant’s arguments directed to Zou is applied as above.
Applicant further argues that Bradbury does not supply the missing elements. Applicant asserts that Bradbury's system is a silica nanoparticle - not a J-aggregate of dye molecules - to which targeting ligands are attached. Bradbury's RGD is conjugated to a silica nanoparticle platform - a structurally and compositionally distinct construct from the claimed MJ-E-D conjugate. Applicant further argues that the proposed combination does not arrive at the claimed invention. Applicant asserts that the proposed modification would yield, at best, a TPP-G-RGD peptide-porphyrin conjugate that self-assembles into nanodots - still a pre-synthesized molecular conjugate that self-assembles into a composite nanodot, not an MJ-E-D conjugate. The fundamental architectural problem remains: there is no pre-formed J-aggregate to which a functional moiety is subsequently attached via a linker. Moreover, if RGD were simply substituted for FF in the monomer, RGD would become a structural self-assembly component of the nanodot (as FF is in Zou) - not a "functional moiety" (D) conjugated via a linker (E) to a pre-existing modified J-aggregate (MJ). D. Applicant further argues that for the same reasons stated in the § 102 response to Zou, claims 16-17 require a functionalized J-aggregate forming dye (not present in either reference); claims 23-25 imply a product formed by salt-induced co-aggregation of mixed dyes (not disclosed or suggested); and claim 28 (D = streptavidin, biotin, RGD, or derivative) depends from claim 14 and requires the MJ-E-D architecture, which is not met.
Applicant’s arguments have been fully considered but are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, it is submitted that Zou teaches the MJ-E-D structure, as set forth above. Bradbury is included to address the use of RGD as a desirable targeting peptide in place of the peptide corresponding to structural element D.
With regard to the assertion that there is no pre-formed J-aggregate to which a functional moiety is subsequently attached via a linker, it is noted that the order in which components of MJ-E-D are formed does not distinguish over the product itself, as set forth above.
Conclusion
No claims are allowed at this time.
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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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
