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 1-21 of G. Bruylants et al., US 17/799,248 (Feb. 10, 2021) are pending. Claims 4, 5 and 11-21 drawn to non-elected Groups (II)-(VII) are withdrawn from consideration pursuant to 37 CFR 1.142(b) as not directed to the elected invention.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 6-10 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 6-10), 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 Claims 4, 5 and 11-21 drawn to non-elected Groups (II)-(VII) are withdrawn from consideration pursuant to 37 CFR 1.142(b).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 obtain a metal-based nanomaterial coated with calix[n]arenes.
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.
Specification at page 3, lines 8-10.
A metal can be any of the metals as defined in the periodic table of the elements, an in particular of the subclasses alkali metals, alkaline earth metals, lanthanides, actinides, transition metals, post transition metals, or metalloids. Preferably, the metal is a transition metal or a post transition metal. Preferably, the metal is selected from the list comprising silver, palladium, gold, platinum, copper, nickel, zinc, cadmium, indium, lead, aluminum, titanium, silicon, tantalum or iron.
A metal oxide is any oxide of the metals as defined above. Preferably, a metal oxide is a transition metal oxide, such as, but not limited to, [titanium] oxide, tantalum oxide, iron oxide, copper oxide, silver oxide, nickel oxide or a post transition metal oxide, such as, but not limited to, silicon oxide, zinc oxide, cadmium oxide, indium oxide, lead oxide or aluminum oxide.
Specification at page 5, lines 21-33 (emphasis added).
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.
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, 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 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 (which the specification indicates is encompassed by heating) 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 controlling the heat (for example, in units of calories) imparted to the reaction mixture (i.e., controlling the reaction mixture’s caloric intake, which would be directly proportional to the reaction mixture’s temperature). MPEP § 2111.
Claim Rejections - 35 USC § 102 (AIA )
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
§ 102(a)(1) Rejection over L. Troian-Gautier et al., 52 Chemical Communications, 10493-10496 (2016) (“Troian-Gautier”)
Claims 1-3 and 6-9 are rejected 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”).
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:
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 (emphasis added). Troian-Gautiers’ synthesis of gold nanoparticles coated with calix[n]arenes (i.e., complexes 3(a)) meets every limitation of claim 1 (including all claim 1 structural limitations, see Claim Interpretation above).
Per the above experimental, the reaction was conducted at 0 °C. The issue is whether Troian-Gautier meets the claim 1 step of “heating the reaction mixture”. As discussed above in Claim Interpretation, the claim 1 term “heating the reaction mixture” is broadly and reasonably interpreted, consistently with the specification, as controlling the heat (for example, in units of calories) imparted to the reaction mixture (i.e., controlling the reaction mixture’s caloric intake, which would be directly proportional to the reaction mixture’s temperature). MPEP § 2111. Troian-Gautier meets this claim limitation by performing the reaction at 0 °C. Therefore claim 1 is anticipated.
Respecting claim 2, the pH of Troian-Gautier reaction mixture would range from neutral to acidic as the reaction progresses to release HCl.
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).1 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 anticipated.
Claim 6 is anticipated because Troian-Gautier employes gold as the metal.
Claim 7 is anticipated because Troian-Gautier’s calix[4]arene-tetra-diazonium salt 2 is a “calix[ 4 ]arene diazonium salt”.
Claim 8 is anticipated because Troian-Gautier employes sodium borohydride as the reducing agent which is a hydride.
Claim 9 is anticipated because Troian-Gautier employes HAuCl4.3H2O, which would necessarily result in water being present in the reaction mixture. In this regard, base claim 1 recites the open-ended transitional phrase “comprising”. The transitional term "comprising" is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. MPEP § 2111.03(I).
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.
Claims 1-3 and 6-10 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 obtain a metal-based nanomaterial coated with calix[n]arenes.
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:
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), 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). 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, 9, and 10, 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, 9, and 10 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 6 is obvious because the above proposed modification of Valkenier employes gold as the metal.
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.
Claim Rejections - 35 USC § 112(a) (Scope of Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-3 and 6-10 are rejected under 35 U.S.C. 112(a) because the specification, while enabling one of skill in the art to make and use the following subject matter (where proposed amendments to claim 1 is indicated by underlined text):
1. A method to synthesize metal-based nanomaterials coated with calix[n]arenes comprising:
placing at least one oxidized metal, selected from the group consisting of silver, palladium, gold, platinum, copper, nickel, zinc, cadmium, indium, lead, titanium, tantalum, aluminum and iron, 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 obtain a metal-based nanomaterial coated with calix[n]arenes.
does not reasonably enable one of skill in the art to make and use the full claim scope of any “metal carbonate” (per claims 1, 4-9, 11, 13-15 and 18) or “gold carbonate” (per claims 2 and 12).
Factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
MPEP. § 2164.01(a); In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988); In re Wright, 999 F.2d 1557, 27 USPQ2d 1510 (Fed. Cir. 1993). The burden is on the examiner to show that the specification as filed and what was well known to one of skill in the art at the time of filing does not reasonably enable the full scope of the claimed invention. MPEP § 2164.05 (citing Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021); In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991).
Claim Breadth and State of the Prior Art/Level of Predictability
As discussed in Claim Interpretation above, the claim 1 term “oxidized metal” is broadly and reasonably interpreted in accordance with the specification as any metal or metal derivative or metalloid or metalloid derivative in a non-null oxidation state. Claims 1-3 and 7-10 encompass any “oxidized metal”. The periodic table comprises 91 metals and six commonly recognized metalloids (boron, silicon, germanium, arsenic, antimony, and tellurium), each of these different elements have different chemical and physical properties.
Claim 1 further does not limit the identity of the reducing agent, which is a very broad genus.
The number of metals, metalloids, and derivatives thereof in a non-null oxidation state (the “oxidized metal” of claim 1) is essentially uncountable. Further, certain metals have properties that appear preclusive to their use in the claimed method. For example, metals such as Nihonium (Nh113) are highly radioactive with half-lie of 0.24 to 20 milliseconds. See M. Murthy "New Members of the Periodic Table." 40-41 (2017) (“Murthy”) (see page 40, 1st paragraph). Several metallic elements have very short half-lives, often in the order of minutes, seconds or even milliseconds. These elements include: Oganesson (0.00018 seconds); Livermorium (0.0061 seconds); Moscovium (0.0087 seconds); Nihonium (0.48 seconds); Mietnerium (0.72 seconds); Flerovium (2.65 seconds); Hassium (9.7 seconds); Darmstadtium (11.1 seconds); Bohrium (17 seconds); Roentgenium (26 seconds); Copernicium (29 seconds); and Seaborgium (2.4 minutes). C. Drahl, Science News (2019). Several metallic elements are radioactive, including members of the actinide series like uranium, plutonium, thorium, and americium, as well as radium, polonium, and francium. A. Bagher et al., 3 International Journal of Renewable and Sustainable Energy, 59-67 (2014), J. Plant et al., Ch. 5 Radioactivity and Radioelements, 115-146 (2011). These elements have unstable nuclei that undergo radioactive decay, emitting radiation. Id. Neither the art of record nor the specification provides guidance in working with such metals in oxized form form, reducing the particle size of such oxidized metals to “nanomaterials”, or reacting such oxidized metals with calix[n]arene diazonium salts.
Also to be considered is that the chemistry of claim 1 is quite complex because the “oxidized metal” must be chosen as one that will react with the correctly chosen reducing agent (in situ) to form nanoparticles, and where the calix[n]arene diazonium salt must also be reduced in the same reaction pot to form a transient, reactive calix[n]arene radical (though loss of N≡N, during the synthesis), which aryl radical in turn reacts with the surface of in situ formed nanoparticles so as to form a covalent bond. Specification at pages 2-3; see also A. Mattiuzzi et al., Nature Communications, 1-8 (2012) (“Mattiuzzi”) (see page 2, col. 2; page 3, col. 1). Thus, many interrelated variables need to be addressed in choosing the claim 1 “oxidized metal” as the claim 1 nanomaterial precursor in the unpredictable art of chemistry.2 In this regard, Mattiuzzi teaches that diazonium coupling of compounds to surfaces to form coatings suffers from a major disadvantage, which is the poor control of layers thickness and regularity and the reactive aryl radicals that are transiently produced attack not only the electrode surface but also already-grafted aryl layers, generally yielding multilayers and ‘cauliflower’-like surfaces, which may result in a loss of desirable properties. Mattiuzzi at page 2, col. 2.
The art teaches that calix[n]arenes have thus far been grafted to only a limited number of surfaces. L. Troian-Gautier et al., 10 Organic & Biomolecular Chemistry, 3624-3637 (2020) (see page 3633, col. 1 “[u]ntil now, calix[4]arenes have been covalently grafted on surfaces that include: gold, pyrolyzed photoresist films (PPF), glassy carbon, glass, germanium, polypropylene, polyethylene terephthalate, polystyrene and gold nanoparticles”).
Guidance in the Specification
The body of the specification provides general guidance only with respect to the claim 1 “oxidized metal”. See specification pages 5-6; Id. at page 5, lines 16-20.
One of ordinary skill’s primary guidance source are the specifications synthetic working examples. Specification at pages 20-39 (Examples 1-11). The working examples employ three calix[4]arenes (i.e., C1, C2, and C3, specification at page 19, lines 1-5). However, the only “oxidized metal” employed in the working examples is silver nitrate for in situ generation of silver nanoparticles. Specification at pages 20-39 (Examples 1-11).
Neither the art of record nor the specification gives much guidance with respect to nanoparticles outside of the metals germanium, gold, and silver and with respect to these metals, the oxidized forms employed are extremely limited (essentially to only to HAuCl4 and AgNO3).
With respect to claim 6, neither the specification nor the art of record gives any guidance to what oxidized forms of the metalloid silicon are useful in the claimed method. One of ordinary skill has no starting point for exploration of oxidized silicon in the claimed method.
The Quantity of Experimentation Needed Is Undue
In the current case, a prima facie case of non-enablement under 35 U.S.C. § 112(a) of claims 1-3 and 6-10 is established because upon balancing the above-discussed factors, the specification at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full claim scope of “oxidized metal”, per claim independent claim 1 or use of any oxidized “silicon” per dependent claim 6.
Neither specification nor the art of record provides guidance with respect to radioactive metals or metals with short half-lives, such as Nihonium (Nh113). These metals clearly present significant challenges in operation within the context of claim 1. Further, the specification guidance is very limited; the only species of oxidized metal exemplified (i.e., silver nitrate). A prima facie case of undue experimentation is demonstrated.
The primary Wands factors considered are claim breadth with respect to “oxidized metal” is the unpredictability with respect to challenging metals (such as radioactive and short half-life metals), and lack of guidance in the specification and art of record on how to employ such challenging metals in the context of clams 1. Dependent claims 2-3 and 6-10 do not limit sufficiently limit the scope of “oxidized metal”. With respect to claim 6, neither the specification nor the art of record gives any guidance to what oxidized forms of the metalloid silicon are useful to generate in situ silicon nanoparticles and thereafter couple with a calix[n]arene diazonium salt. One of ordinary skill has no starting point for exploration of oxidized silicon in the claimed method.
As noted above, claim 1 is quite complex because the “oxidized metal” must be chosen as one that will react with the correctly chosen reducing agent (in situ) to form nanoparticles, and where the calix[n]arene diazonium salt must also be reduced in the same reaction pot to form a transient, reactive calix[n]arene radical (though loss of N≡N, during the synthesis), which aryl radical in turn reacts with the surface of in situ formed nanoparticles so as to form a covalent bond. Specification at pages 2-3; see also A. Mattiuzzi et al., Nature Communications, 1-8 (2012) (“Mattiuzzi”) (see page 2, col. 2; page 3, col. 1). Thus, many interrelated variables need to be addressed in choosing the claim 1 “oxidized metal” as the claim 1 nanomaterial precursor in the unpredictable art of chemistry. In this regard, Mattiuzzi teaches that diazonium coupling of compounds to surfaces to form coatings suffers from a major disadvantage, which is the poor control of layers thickness and regularity and the reactive aryl radicals that are transiently produced attack not only the electrode surface but also already-grafted aryl layers, generally yielding multilayers and ‘cauliflower’-like surfaces, which may result in a loss of desirable properties. Mattiuzzi at page 2, col. 2.
Conclusion
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 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).
2 The art of chemical reactions is traditionally considered unpredictable. See, In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).