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 .
DETAILED ACTION
Claims 1-4, 7-9, and 11-21 of G. Bruylants et al., US 17/799,248 (Feb. 10, 2021) are pending. Claims 4 and 11-21 drawn to non-elected Groups (II)-(VII) are withdrawn from consideration pursuant to 37 CFR 1.142(b) as not directed to the elected invention. Claims 1-3 and 7-9 are under examination on the merits and are rejected.
Election/Restrictions
Pursuant to the restriction requirement, Applicant elected Group I, (now pending claims 1-3 and 7-9), drawn to a method to synthesize metal-based nanomaterials coated with calix[n]arenes, without traverse, in the reply filed on May 23, 2025. Claims 4 and 11-21 drawn to non-elected Groups (II)-(VII) are maintained as withdrawn from consideration pursuant to 37 CFR 1.142(b). The restriction requirement is maintained as FINAL
Claim Interpretation
Examination requires claim terms first be construed in terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim. See, MPEP § 2111. Under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. See MPEP § 2111.01. It is also appropriate to look to how the claim term is used in the prior art and dictionaries. MPEP § 2111.01 (III).
Structural Interpretation of Claim 1
Claim 1 recites as follows, without providing structural definition to the claimed calix[n]arenes:
1. A method to synthesize metal-based nanomaterials coated with
calix[n]arenes comprising:
placing at least one oxidized metal with at least one calix[n]arene diazonium salt in the presence of a reducing agent in a solvent, and
heating the reaction mixture to between 15°C and 150 °C to obtain a metal-based nanomaterial coated with calix[n]arenes; and
wherein said metal is selected from the group consisting of silver, palladium, gold, platinum, copper, and iron.
The specification defines “oxidized metal” as follows:
An oxidized metal refers to a metal with metal or metal derivative having a non-null oxidation state. Preferably, an oxidized metal refers to a metal having a positive oxidation state. It can be a metal salt or a metal oxide.
The claim 1 term “oxidized metal” is interpreted in accordance with the specification definition as any metal or metal derivative or metalloid or metalloid derivative in a non-null oxidation state, wherein said metal is selected from the group consisting of silver, palladium, gold, platinum, copper, and iron.
The specification defines “nanomaterial” as follows:
A nanomaterial according to the present invention is a particulate material (nanoparticle) having at least one dimension in the nanometric range, i.e. between 1 and 999 nm, preferably between 5 and 800 nm, still preferably between 10 and 500 nm, preferably below 250 nm or below 150 nm or below 100 nm as generally accepted for a nanomaterial.
Specification at page 6, lines 11-14 (emphasis added).
The claim 1 term “nanomaterial” is interpreted in accordance with the specification definition.
Respecting structural interpretation of claim 1 calix[n]arenes, the specification provides an explicit definition of the claim 1 term “calix[n]arene diazonium salt”. Specification at page 7, lines 3-8. In view of the specification definition, the broadest reasonable interpretation of the claim 1 term "calix[n]arene diazonium salt", consistent with the specification, is set forth below:
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The specification provides a definition for “calix[n]arenes bound to the surface of the metal-based nanomaterial”, which is reasonably interpreted to correlate with the claim 1 term “metal-based nanomaterial coated with calix[n]arenes”. Specification at page 8, line 10 to page 9, line 11.
In view of the specification definition of “calix[n]arenes bound to the surface of the metal-based nanomaterial”, the broadest reasonable interpretation of the claim 1 term “metal-based nanomaterial coated with calix[n]arenes”, consistent with the specification, is formula (II) below:
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Specification at page 8, line 10 to page 9, line 11. Where any of Z1-Z6 can be a listed variable alternative or be an indirect or direct covalent bond to the metal surface. Specification at page 9, lines 1-5. Consistent with the above interpretation, the specification summarizes the claim 1 process as follows, where “MC” corresponds to the claimed “calix[n]arenes bound to the surface of the metal-based nanomaterial”:
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Specification at page 3, lines 17-21.
Interpretation of the Claim 1 Step of “heating the reaction mixture”
With respect to the meaning of “heating” in the context of claim 1, claim 1 recites:
Claim 1 . . . heating the reaction mixture to between 15°C and 150 °C to obtain a metal-based nanomaterial coated with calix[n]arenes . . .
The specification teaches that:
Heating is preferably performed under mixing, at temperatures comprised between 15 °C and 150 °C, preferably between 20°C and 120 °C, preferably between 25 °C and 100 °C, preferably between 40 and 80 °C and still preferably around 60 °C.
It was observed by the applicants that the reaction temperature has an impact on the particle size distribution. A reaction temperature of around 60°C leads to a narrow size distribution.
Specification at page 4, lines 15-20 (emphasis added). Thus, the specification essentially indicates that the meaning of “heating” relates to controlling the reaction temperature. The specification further indicates that “heating” encompasses temperature below room temperature (i.e., room temperature in the art of chemistry generally means about 20 °C to about 25 °C). See e.g., Hawley's Condensed Chemical Dictionary, page 1201 (16th ed., 2016, R.J. Larrañaga ed.). For example, practicing claim 1 at a temperature of 15 °C (60 °C F, which is lower than room temperature) would require a cooling bath. In view of the forgoing, the claim 1 term “heating the reaction mixture” is broadly and reasonably interpreted, consistently with the specification, as maintaining the temperature within a range of between 15 °C and 150 °C. MPEP § 2111.
Withdrawal Claim Rejections - 35 USC § 102 (AIA )
Rejection of claims 1-3 and 6-9 under 35 U.S.C. 102(a)(1) as being anticipated by L. Troian-Gautier et al., 52 Chemical Communications, 10493-10496 (2016) (“Troian-Gautier”) is withdrawn in view of Applicant’s amendment.
Withdrawal Claim Rejections - 35 USC § 112(a) (Scope of Enablement)
Rejection of claims 1-3 and 6-10 are rejected under 35 U.S.C. 112(a) as non-enabled is withdrawn in view of Applicant’s amendments.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
FIRST § 103 REJECTION
Claims 1-3 and 7-9 are rejected under AIA 35 U.S.C. 103 as being unpatentable over L. Troian-Gautier et al., 52 Chemical Communications, 10493-10496 (2016) (“Troian-Gautier”).
Troian-Gautier teaches that calix-Au nanoparticles (3a)-(3d) were synthesized by reducing HAuCl4 with NaBH4 in the presence of calix[4]arenetetra-diazonium 2 in acetonitrile (referring to Scheme 1). Troian-Gautier at page 10493, col. 2.
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Troian-Gautier at page 10494, Scheme 1. Troian-Gautier provides the following experimental procedures for nanoparticles 3a and 3b:
Synthesis of gold nanoparticles 3a in presence of calix[4]arene-tetra-diazonium salt 2.
HAuCl4.3H2O (25 mg, 0.0635 mmol, 1 equiv.) was dissolved in acetonitrile (25 mL) and a solution of calix[4]arene-tetra-diazonium salt 2 (24 mg, 0.0315 mmol, 0.5 equiv.) in acetonitrile (25 mL) was added. The reaction mixture was stirred vigorously at 0°C under Ar and an aqueous solution of NaBH4 (0.5 mL, 6.1 mg, 0.161 mmol, 2.5 equiv.) was added dropwise.
The color of the reaction mixture changed from yellow to dark ruby. After 2 hours of vigorous stirring, the reaction mixture was centrifuged at 5000 rpm for 20 min. The gold nanoparticles were washed by resuspension in NaOH (1 M) and precipitation with HCl (1 M) (two centrifugation cycles using 30 mL) and with water (1 × 30 mL) to obtain gold nanoparticles 3a stabilized by calix[4]arenes (18 mg). The gold nanoparticles 3a were dispersed in NaOH (1 M, 40 mL) and stored at 4°C for several weeks, without exhibiting any noticeable aggregation.
15 nm calixarene-stabilized AuNPs 3b by grafting of 2.
AuNPs were synthesized as reported previously using a modified Turkevich method and dialyzed against a 1 mM solution of citrate.
To the resulting gold nanoparticles (15-19 nm depending on the batch, 24 mL, 25 nM, 0.6 nmol) was added a solution of NaBH4 (100 μL, 0.3 M, 0.030 mmol)1 in water, followed by the slow addition of a solution of calix[4]arene-tetra-diazonium salt 2 (45.9 mg, 0.060 mmol) in water (6 mL), resulting in effervescence of the red colloidal suspension.
The reaction mixture was stirred overnight at room temperature, followed by the centrifugation of the mixture.
The functionalized AuNPs 3b were resuspended in 1 mM NaOH and collected by centrifugation (30 min at 15000 rpm) 6 times. For the TGA experiments, the AuNPs were washed an additional 4 times with water. AuNPs 3b were stored in water at room temperature.
Troian-Gautier at page S-7 (emphasis added).
Differences between Troian-Gautier and Claim 1
Troian-Gautier’s synthesis of gold nanoparticles coated with calix[n]arenes (i.e., complexes 3(a)) meets every limitation of claim 1 except the claim 1 heating limitation.
Claim 1 . . . heating the reaction mixture to between 15°C and 150 °C to obtain a metal-based nanomaterial coated with calix[n]arenes . . .
because Troian-Gautier performs the reaction at 0 °C.
In this regard, it is noted that Troian-Gautier’s second procedure (synthesis of gold nanoparticles coated with calix[n]arenes (3b)), although conducted at room temperature and thereby meeting the above claim 1 heating limitation, does not employ oxidized gold; rather the gold nanoparticles are in a zero-oxidation state.
P. Blond et al., 34 Langmuir, 6021-6027, (2018) (“Blond”) and S. Nimse, 42 Chemical Society Reviews, 366-386 (2013) (“Nimse”)
Blond and Nimse are cited here as motivating one of ordinary skill to further explore Troian-Gautier’s synthetic methodology for functionalizing metal nanoparticles with calix[n]arenes bearing diazonium groups due to the application of the resulting metal-based nanomaterial coated with calix[n]arenes in the development of biosensors and in the field of biology, biotechnology, and drug discovery.
Blond discloses that biosensors that can determine protein concentration and structure are highly desired for biomedical applications. Blond at Abstract. Blond discloses that a major challenge in the development of such biosensors is the modification of surfaces by a robust organic monolayer able to specifically interact with a protein and displaying antifouling properties to prevent nonspecific adsorption phenomena. Blond at page 6021, col. 1. Blond discloses that robust monolayers of calix[4]arenes bearing oligo- (ethylene glycol) (oEG) chains, which were grafted on germanium and gold surfaces via their tetradiazonium salts, where the organic coating by oEGylated calix[4]arenes provides remarkable antifouling properties, opening the way for the design of germanium- or gold-based biosensors. Blond at Abstract. Blond’s Scheme 1 is reproduced below.
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Blond at page 6022 (Scheme1).
Nimse is a review teaching that functionalized calixarene derivatives exhibit remarkable properties towards organic and bioorganic molecules, where, the ability of calixarene derivatives to form stable complexes with biomolecules allows them to be applied for the development of biosensors and in the field of biology, biotechnology, and drug discovery. Nimse at Abstract. For example, Nimse teaches Scheme 2, showing immobilization of proteins on the slide glass modified with the calix[4]crown-5 derivatives 3, 4. Nimse at page 368, Scheme 2.
Obviousness Rationale
Claims 1-3 and 7-9 are obvious over Troian-Gautier for the following reasons. The claimed reaction temperature difference between Troian-Gautier (0 °C) and the claimed temperature of:
Claim 1 . . . heating the reaction mixture to between 15°C and 150 °C to obtain a metal-based nanomaterial coated with calix[n]arenes . . .
is not a patentable distinction. One of ordinary skill in the art is motivated (in view of the utility of to metal-based nanomaterial coated with calix[n]arenes in the development of biosensors and in the field of biology, biotechnology, and drug discovery) to conduct Troian-Gautier’s synthesis of 3a at higher temperatures (for example, room temperature) thereby meeting each and every limitation of claim 1. For example, one of ordinary skill is motivated to optimize Troian-Gautier’s temperature to ensure a complete reaction, achieve a shorter reaction time, or simply for reaction economy (i.e., not employ a cooling bath where such is not needed).
One of ordinary skill is motivated to develop workable or optimum ranges for result-effective parameters, where Applicant can rebut a prima facie case of obviousness by showing the criticality (unexpected result) of the range. MPEP § 2144.05; see also, In re Boesch, 617 F.2d 272,276 (CCPA 1980); In re Aller, 220 F.2d 454, 456 (CCPA 1955) (generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical).1,2
In regard to reaction temperature, Troian-Gautier’s second procedure (see above, synthesis of gold nanoparticles coated with calix[n]arenes (3b)), is conducted room temperature and thereby meeting the above claim 1 heating limitation, but does not employ oxidized gold; rather the gold nanoparticles are in a zero-oxidation state. Troian-Gautier at page S-7. As such, one of ordinary skill has a reasonable expectation that optimization to higher temperatures (for example room temperature) are feasible. MPEP § 2143.02(I).
Claim 2 is obvious for the following reasons. Respecting claim 2, the pH of Troian-Gautier reaction mixture would range from neutral to acidic as the reaction progresses to release HCl according the following reaction.
HAuCl4 + NaBH4 → Au (nanoparticles) + HCl + BH4 and sodium chloride salts.
H. Mahdi et al., IOP Conference Series: Materials Science and Engineering, 1-5 (2019). Thus, at some point during the Troian-Gautier reaction, the claim 1 step of “adjusting the pH of the reaction mixture at a value between 3.5 and 10” would be accomplished and this further limitation of claim 2 is met. MPEP § 2112(V) (citing In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977).3 It is noted that pH measurement in non-aqueous media is not straightforward. See, e.g., S. Rondinini et al., 374 Anal Bioanal Chem, 813-816 (2002).
Respecting claim 3, Troian-Gautier employes 0.5 equivalents of calix[4]arene-tetra-diazonium salt 2 to 1.0 equivalents of HAuCl4.3H2O for a “molar ratio of oxidized metal to the calix[ n ]arene diazonium salt” of 2, which falls within the claimed range. Claim 3 is therefore obvious.
Claim 7 is obvious because Troian-Gautier’s calix[4]arene-tetra-diazonium salt 2 is a “calix[ 4 ]arene diazonium salt”.
Claim 8 is obvious because Troian-Gautier employes sodium borohydride as the reducing agent which is a hydride.
The further limitations of claim 9 are met because Troian-Gautier employes HAuCl4.3H2O and “and an aqueous solution of NaBH4 (0.5 mL, 6.1 mg, 0.161 mmol, 2.5 equiv.) was added dropwise”, thus water is present in the reaction mixture as a solvent.
Applicant’s Argument
Applicant argues that in Troian-Gautier, the temperature used is 0°C whereas in claim 1 the temperature ranges from 15°C to 150°C and this temperature is obtained via heating. Therefore, since clearly Troian-Gautier does not teach heating and the reaction is at such a lower temperature, there is no feasibility that it would be obvious to raise the temperature of Troian-Gautier. Applicant argues that the technical effect brought by the heating is demonstrated in the patent application as published on the pages 23-24 in the Comparative Example 2. Namely, with the method used in Troian-Gautier (i.e., with the temperature of 0°C), the particles were either degraded (see, two first lines of the table) or were less abundant and with a broad size distribution. However, Applicant argues that the claimed method allows producing more particles of nanomaterial with a sharp size distribution and also in more stable way. Hence, it can be concluded that the claimed method is an improved method of production of nanomaterials.
Examiner Response
It is first noted that Applicant does not appear to be arguing unexpected results (criticality of temperature), rather a mere improvement. But in any case, here the Examiner cannot make a determination of unexpected results because specification comparative Example 2 prepares silver core nanoparticles (where the silver salt used is not disclosed), whereas Troian-Gautier prepares gold nanoparticles using HAuCl4 as the oxidized metal. Troian-Gautier makes no mention of silver. Applicant has therefore not made a comparison with the closest prior art as required. MPEP § 716.02(e). Further, where the comparison is not identical with the reference disclosure, deviations therefrom should be explained. MPEP § 716.02(e). Here, Applicant has provided no explanation as to why the specification’s results with the unnamed silver salt would extend to Troian-Gautier’s gold nanoparticles using HAuCl4. Still further, Applicant’s proffered results (directed only to sliver) are clearly not commensurate with the claimed scope of metals and would therefore be insufficient to overcome an obviousness rejection. MPEP § 716.03(a).
This argument is further not persuasive because, as discussed in more detail above, one of ordinary skill in the art is motivated to conduct Troian-Gautier’s synthesis of 3a at higher temperatures (for example, room temperature). For example, one of ordinary skill is motivated to optimize Troian-Gautier’s temperature to ensure a complete reaction, achieve a shorter reaction time, or simply for reaction economy (i.e., not employ a cooling bath where such is not needed). In re Aller, 220 F.2d 454, 456 (CCPA 1955) (generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical).
SECOND § 103 REJECTION
Claims 1-3 and 7-9 are rejected under AIA 35 U.S.C. 103 as being unpatentable over H. Valkenier et al., 33 Langmuir, 8253-8259 (2017) (“Valkenier”) in combination with L. Troian-Gautier et al., 52 Chemical Communications, 10493-10496 (2016) (“Troian-Gautier”) in further view of C. Lin et al., 18 Molecules, 12609-12620 (2013) (“Lin”); Y. Hayashi, 7 Chemical Science, 866-880 (2016) (“Hayashi”); P. Blond et al., 34 Langmuir, 6021-6027, (2018) (“Blond”) and S. Nimse, 42 Chemical Society Reviews, 366-386 (2013) (“Nimse”).
H. Valkenier et al., 33 Langmuir, 8253-8259 (2017) (“Valkenier”)
Valkenier teaches synthesis of calix[4]arene-tetradiazonium decorated by four oligo(ethylene glycol) chains on the small rim, which upon grafting gave AuNPs with excellent stability due to the C−Au bonds. Valkenier at Abstract. Valkenier teaches that:
An alternative to the labile binding of carboxylates, amines, and thiols to gold surfaces is grafting via covalent C−Au bonds. These can be obtained using organic ligands bearing an aryl-diazonium group. This group can be reduced in situ, generating an highly active aryl radical that readily reacts with the gold surface. A drawback of this method is that it often leads to the formation of multilayers because the generated aryl radicals easily react with the already grafted aryl groups. However, this can be prevented by using calix[4]arene-tetradiazonium compounds whose structure and geometry do not allow any additional grafting.
These cone-shaped macrocycles can be grafted via multiple C−Au bonds, leading to a remarkably robust ligand shell on surfaces and on AuNPs. Furthermore, because the grafting of these calix[4]arenes via C−Au bonds is irreversible, homogeneous mixtures of calixarenes can be grafted.
Valkenier at page 8254, col. 1 (emphasis added).
Valkenier teaches that AuNPs functionalized with peptides or antibodies are useful for the detection of proteins or viruses. Valkenier at page 8253, col. 1.
Valkenier teaches the following experimental preparation of Grafting of AuNPs-calix(oEG)4:
Grafting of AuNPs-calix(oEG)4 on large scale for TGA.
To the gold nanoparticles (17 nm, 21.5 mL, 21 nM, 0.45 nmol) in a glass vial was added a solution of NaBH4 (90 μL, 0.3 M, 0.027 mmol) in water upon magnetic stirring.
The acidic solution of calix(oEG)4(N2+)4 2b (5.4 mL, 10 mM, 0.054 mmol) was neutralised by addition of phosphate buffer (6 mL, 0.2 M, pH 6.7) to obtain a final pH of 6.4.
The calixarene solution was added dropwise to the AuNPs, resulting in effervescence of the red colloidal suspension.
The reaction mixture was stirred overnight (20 h), followed by the centrifugation of the mixture for 30 minutes at 16500 G, after which the supernatant was removed.
The functionalised AuNPs were washed by 8 cycles of resuspension in NaOH (15 mL, 1 mM), subsequent centrifugation (30 min at 16500 G), and removal of the supernatant.
For the TGA experiments, the AuNPs were washed an additional 4 times with water (1.5 mL).
The functionalised AuNPs were stored in water at room temperature and further concentrated to ~40 μL prior to the TGA measurements.
Valkenier at page S8.
Per Valkenier Scheme 1, the above experimental is summarized as follows. Valkenier at page 8254 (Scheme 1).
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Differences between Claim 1 and Valkenier
Claim 1 differs from Valkenier in that Valkenier does not teach the claim 1 step that is bolded, italic below:
1. A method to synthesize metal-based nanomaterials coated with
calix[n]arenes comprising:
placing at least one oxidized metal with at least one calix[n]arene diazonium salt in the presence of a reducing agent in a solvent, and
heating the reaction mixture to between 15°C and 150 °C to obtain a metal-based nanomaterial coated with calix[n]arenes; and
wherein said metal is selected from the group consisting of silver, palladium, gold, platinum, copper, and iron.
That is, claim 1 requires combining the oxidized metal, the calix[n]arene diazonium salt, and the reducing agent, form the final metal-based nanomaterial coated with calix[n]arenes; whereas Valkenier teaches synthesizing the gold nanoparticles first and thereafter adding the calix[4]arene-tetra-diazonium salt (2) and the reducing agent NaBH4 to the pre-synthesized gold nanoparticles so as to reductively couple the calix[4]arene-tetra-diazonium salt (2) to form the final gold nanoparticles coated with calix[4]arenes.
L. Troian-Gautier et al., 52 Chemical Communications, 10493-10496 (2016) (“Troian-Gautier”)
Troian-Gautier teaches that calix-Au nanoparticles (3a)-(3d) were synthesized by reducing HAuCl4 with NaBH4 in the presence of calix[4]arenetetra-diazonium 2 in acetonitrile (referring to Scheme 1). Troian-Gautier at page 10493, col. 2.
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Troian-Gautier at page 10494, Scheme 1. Troian-Gautier provides the following experimental, which as discussed above in the § 102 section anticipates claims 1-3 and 6-9:
Synthesis of gold nanoparticles 3a in presence of calix[4]arene-tetra-diazonium salt 2.
HAuCl4.3H2O (25 mg, 0.0635 mmol, 1 equiv.) was dissolved in acetonitrile (25 mL) and a solution of calix[4]arene-tetra-diazonium salt 2 (24 mg, 0.0315 mmol, 0.5 equiv.) in acetonitrile (25 mL) was added.
The reaction mixture was stirred vigorously at 0°C under Ar and an aqueous solution of NaBH4 (0.5 mL, 6.1 mg, 0.161 mmol, 2.5 equiv.) was added dropwise. The color of the reaction mixture changed from yellow to dark ruby. After 2 hours of vigorous stirring, the reaction mixture was centrifuged at 5000 rpm for 20 min. The gold nanoparticles were washed by resuspension in NaOH (1 M) and precipitation with HCl (1 M) (two centrifugation cycles using 30 mL) and with water (1 × 30 mL) to obtain gold nanoparticles 3a stabilized by calix[4]arenes (18 mg). The gold nanoparticles 3a were dispersed in NaOH (1 M, 40 mL) and stored at 4°C for several weeks, without exhibiting any noticeable aggregation.
Troian-Gautier at page S-7. Troian-Gautier provides the following alternative experimental:
15 nm calixarene-stabilized AuNPs 3b by grafting of 2.
AuNPs were synthesized as reported previously using a modified Turkevich method and dialyzed against a 1 mM solution of citrate.
To the resulting gold nanoparticles (15-19 nm depending on the batch, 24 mL, 25 nM, 0.6 nmol) was added a solution of NaBH4 (100 μL, 0.3 M, 0.030 mmol)1 in water, followed by the slow addition of a solution of calix[4]arene-tetra-diazonium salt 2 (45.9 mg, 0.060 mmol) in water (6 mL), resulting in effervescence of the red colloidal suspension.
The reaction mixture was stirred overnight at room temperature, followed by the centrifugation of the mixture.
The functionalized AuNPs 3b were resuspended in 1 mM NaOH and collected by centrifugation (30 min at 15000 rpm) 6 times. For the TGA experiments, the AuNPs were washed an additional 4 times with water. AuNPs 3b were stored in water at room temperature.
Troian-Gautier at page S-7. These alternative experimental procedures apprise one of ordinary skill that the desired gold nanoparticles coated with calix[4]arenes prepared through the reductive grafting of a calix[4]arene-tetra-diazonium salt can be accomplished with by either of the following two alternative procedures.
(1) (Per the first one-pot procedure) Combining the HAuCl4.3H2O (the claim 1 oxidized metal), the calix[4]arene-tetra-diazonium salt (2), and the reducing agent NaBH4, together in a single reaction pot, which the HAuCl4.3H2O is reduced to gold nanoparticles, which thereafter reductively couple with the calix[4]arene-tetra-diazonium salt (2) to form the final gold nanoparticles coated with calix[4]arenes; or
(2) (Per the second grafting procedure) First synthesizing the gold nanoparticles and thereafter adding the calix[4]arene-tetra-diazonium salt (2) and the reducing agent NaBH4 to the pre-synthesized gold nanoparticles so as to reductively couple the calix[4]arene-tetra-diazonium salt (2) to form the final gold nanoparticles coated with calix[4]arenes.
C. Lin et al., 18 Molecules, 12609-12620 (2013) (“Lin”)
Lin teaches that gold nanoparticles (Au NPs) were prepared by reducing HAuCl4 with NaBH4. Lin at Abstract. Lin provide the following experimental procedure, where water is the solvent.
3.2.1. Preparation of Au NPs
Au NPs with different sizes were prepared by a reported method [27]. HAuCl4·4H2O (0.06 mmol) and PVP (10.0 mg) were dissolved in deionized water (95.0 g) in a round-bottom flask, followed by stirring for 30 min. Aqueous NaBH4 (5 mL) containing 1.0 mmol NaBH4 was then injected. The color of solution turned to dark red instantly. The solution was further stirred for 1 h to obtain 5.7 nm Au NPs. Au NPs with average sizes of 1.7, 3.4, and 8.2 nm were obtained by adding 0.4, 0.5, and 1.1 mmol NaBH4, respectively.
Lin at page 12617. Lin teaches one of ordinary skill that water is a suitable solvent for formation of gold nanoparticles by reduction of HAuCl4·4H2O suing NaBH4 where the solvent is water.
Y. Hayashi, 7 Chemical Science, 866-880 (2016) (“Hayashi”)
Hayashi teaches that the one-pot synthesis of a target molecule in the same reaction vessel is widely considered to be an efficient approach in synthetic organic chemistry. Hayashi at Abstract. Hayashi teaches that “telescoped”, “one pot” reactions, where intermediates are not isolated improve reaction economy (reduces expense) because intermediate workups are avoided. Hayashi at page 868, col. 1 (4). Hayashi discusses criteria for effective one-pot synthesis of, including the case where the intermediate compound is unstable or hazardous. Hayashi at page 868, col. 2 (6.1).
P. Blond et al., 34 Langmuir, 6021-6027, (2018) (“Blond”) and S. Nimse, 42 Chemical Society Reviews, 366-386 (2013) (“Nimse”)
Blond and Nimse are cited here as motivating one of ordinary skill to further explore Valkenier’s and Troian-Gautier’s synthetic methodology for functionalizing metal nanoparticles with calix[n]arenes bearing diazonium groups due to the application of the resulting metal-based nanomaterial coated with calix[n]arenes in the development of biosensors and in the field of biology, biotechnology, and drug discovery.
Blond discloses that biosensors that can determine protein concentration and structure are highly desired for biomedical applications. Blond at Abstract. Blond discloses that a major challenge in the development of such biosensors is the modification of surfaces by a robust organic monolayer able to specifically interact with a protein and displaying antifouling properties to prevent nonspecific adsorption phenomena. Blond at page 6021, col. 1. Blond discloses that robust monolayers of calix[4]arenes bearing oligo- (ethylene glycol) (oEG) chains, which were grafted on germanium and gold surfaces via their tetradiazonium salts, where the organic coating by oEGylated calix[4]arenes provides remarkable antifouling properties, opening the way for the design of germanium- or gold-based biosensors. Blond at Abstract. Blond’s Scheme 1 is reproduced below.
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Blond at page 6022 (Scheme1).
Nimse is a review teaching that functionalized calixarene derivatives exhibit remarkable properties towards organic and bioorganic molecules, where, the ability of calixarene derivatives to form stable complexes with biomolecules allows them to be applied for the development of biosensors and in the field of biology, biotechnology, and drug discovery. Nimse at Abstract. For example, Nimse teaches Scheme 2, showing immobilization of proteins on the slide glass modified with the calix[4]crown-5 derivatives 3, 4. Nimse at page 368, Scheme 2.
Obviousness Rational
One of ordinary skill is motivated to further explore Valkenier’s and Troian-Gautier’s synthetic methodology for functionalizing metal nanoparticles with calix[n]arenes bearing diazonium groups in view of Blond’s and Nimse’s teachings of the utility of the resulting metal-based nanomaterial coated with calix[n]arenes in the development of biosensors and in the field of biology, biotechnology, and drug discovery. In this regard, Valkenier teaches that AuNPs functionalized with peptides or antibodies are useful for the detection of proteins or viruses. Valkenier at page 8253, col. 1.
Toward this end, one of ordinary skill is motivated to modify the following procedure of Valkenier for Grafting of AuNPs-calix(oEG)4 on large scale for TGA. (Valkenier at page S8), to a one-pot procedure by combining the HAuCl4.3H2O (the claim 1 oxidized metal), the calix(oEG)4(N2+)4 2b, and the reducing agent NaBH4, together in a single reaction pot at room temperature, whereby the HAuCl4.3H2O is reduced to gold nanoparticles in situ, with a reasonable expectation that thereafter the calix(oEG)4(N2+)4 2b will reductively couple with the in situ formed gold nanoparticles to form desired gold nanoparticles coated with calix[4]arenes.
One of ordinary skill has a reasonable expectation of success because Troian-Gautier teaches such a one pot process with calix[4]arene-tetra-diazonium salt (2) (albeit with acetonitrile as the solvent with some water from the aqueous NaBH4 addition). Troian-Gautier at page S-7. One of ordinary skill has reasonable expectation of success that water is a suitable solvent (as taught by Valkenier) for such one-pot process in view of Lin’s teaching that water is a suitable solvent for formation of gold nanoparticles by reduction of HAuCl4·4H2O suing NaBH4 where the solvent is water. Lin at page 12617.
One of ordinary skill is motived to so modify Valkenier in view of Hayashi’s teaching that the one-pot synthesis of a target molecule in the same reaction vessel is widely considered to be an efficient approach in synthetic organic chemistry. Hayashi at Abstract. Each and every limitation of claim 1 is met by the above-proposed modification of Valkenier, conducted at room temperature, which meets the claim 1 step of “heating the reaction mixture” for the same reasons discussed above in the § 102 rejection.
Respecting claims 2 and 9, the pH of the buffered Valkenier aqueous reaction mixture (pH about 6.4), the solvent is water, and reaction mixture temperature is room temperature. Each and every further limitation of claims 2 and 9 are therefore met by the above proposed modification of Valkenier.
Respecting claim 3, Troian-Gautier employes 0.5 equivalents of calix[4]arene-tetra-diazonium salt 2 to 1.0 equivalents of HAuCl4.3H2O for a “molar ratio of oxidized metal to the calix[ n ]arene diazonium salt” of 2, which falls within the claimed range. Claim 3 is therefore obvious because this is a natural starting point for concentration optimization. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. MPEP § 2144.04(II)(A) (citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) ("[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation”)).
Claim 7 is obvious because in the above proposed modification of Valkenier involves a calix[4]arene-tetra-diazonium salt which is a “calix[ 4 ]arene diazonium salt”.
Claim 8 is obvious because the above proposed modification of Valkenier employes sodium borohydride as the reducing agent which is a hydride.
Applicant’s Argument
Applicant’s argument regarding reaction temperature were fully addressed above.
Applicant further argues that Valkenier is a different method, and thereby cannot be a
basis for modifying the reaction of Troian-Gautier.
Examiner Response
This argument is not persuasive for the following reasons. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. MPEP § 2145(IV). Applicant has not specifically stated the differences between Valkenier and the claimed method that prevent one of ordinary skill to combine Valkenier with the secondary references to arrive at the claimed invention. The § 103 already acknowledges that Valkenier differs from the claimed method in that claim 1 requires combining the oxidized metal, the calix[n]arene diazonium salt, and the reducing agent, form the final metal-based nanomaterial coated with calix[n]arenes; whereas Valkenier teaches synthesizing the gold nanoparticles first and thereafter adding the calix[4]arene-tetra-diazonium salt (2) and the reducing agent NaBH4 to the pre-synthesized gold nanoparticles so as to reductively couple the calix[4]arene-tetra-diazonium salt (2) to form the final gold nanoparticles coated with calix[4]arenes. The above rationale makes it clear why Valkenier was cited as part of a reference combination and why one of ordinary skill is motivated to combine its teachings so as to arrive at the claimed invention.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. MPEP § 716.02(d) (citing In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960)).
2 The specification teaches that the reaction temperature has an impact on the particle size distribution. And a reaction temperature of around 60°C leads to a narrow size distribution. Specification at page 4, lines 15-20; see also, specification at page 22, lines 35-32.
3 Where the Patent Office has reason to believe that a limitation asserted to be critical for establishing novelty in the claimed subject matter may, in fact, be an inherent characteristic of the prior art, it possesses the authority to require the applicant to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on. In re Schreiber, 128 F.3d 1473, 1478 (Fed. Cir. 1997) (citing In re Swinehart, 58 C.C.P.A. 1027, 439 F.2d 210, 212, 169 USPQ 226, 228 (CCPA 1971) (emphasis added).
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