DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 07/30/2025 has been entered.
Claims 23, 25-26, 30-34, 36-37 and 40-48 are pending in this application.
Applicant’s amendment to the claims filed 07/30/2025 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s Declaration under 37 CFR 1.132 filed 07/30/2025 is acknowledged and has been fully considered.
Applicant’s remarks filed on 07/30/2025 in response to the final rejection mailed on 03/31/2025 is acknowledged and has been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election
The elected subject matter is
Group I, corresponding to claims 23, 25-26, 30-34, 36-37, 40 and 46-48 drawn to the technical feature of a method for conjugating a free thiol group of a moiety of a biomolecule, comprising contacting the biomolecule with a gold-donor agent to form a S-Au-S bond, characterized in that the gold-donor agent is halogen(triarylphosphine)gold (I),
elected with traverse in the reply filed 06/14/2024.
Claims 41-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on 06/14/2024.
Claims 23, 25-26, 30-34, 36-37, 40 and 46-48 are being examined on the merits.
Response to remarks: Beginning on p. 15 para 3 of Applicant’s response to the Final rejection mailed 03/31/2025; Applicant contends claims 41-45 share the same technical features as claim 23 as they are dependent from claim 23, and therefore the inventions should be rejoined.
Applicants remarks are considered and found not convincing. As set forth in the requirement for restriction mailed 04/17/2024 and updated to reflect the amendments to the claims:
The invention of Group I corresponding to claims 23, 25-26, 30-34, 36-37, 40 and 46-48 is drawn to the technical feature of a method of conjugating a free thiol group to a moiety of a biomolecule, and the invention of Group II corresponding to claims 41-45 is drawn to the technical feature of a modified protein cage.
The inventions of Groups I and II lack unity of invention because even though the inventions of these groups share the technical feature of a method of conjugating a free thiol group of a moiety of a TRAP protein, comprising (i) providing a TRAP protein with a cysteine residue on the outer perimeter of the TRAP protein at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus, (ii) contacting the TRAP protein with a gold-donor agent to form a S-Au-S bond, characterized in that the gold-donor agent is halogen(triarylphosphine)gold(I), wherein the moiety with the free thiol group is the cysteine moiety, and (iii) generating a protein cage biomolecule complex, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Igashiri-Kamiyama et al. (Dalton Trans, 2011, 40:7249; cited on the IDS filed 05/25/2021), Caddy et al. (Zeitshrift fur Naturforschung B, 2007, 62:460; cited on the IDS submitted 05/25/2021), Heddle et al. (Small, 2007, 11:1950; cited on the Form PTO-892 mailed 09/04/2024) and evidentiary reference UniProt Accession No. MTRB_GEOSE (2 pages 11/02/2016; cited on the Form PTO-892 mailed 03/31/2025) as described in the rejections below. Therefore, the inventions of Groups I and II lack of unity of invention.
Claim Objections
The objection to claim 46 is withdrawn in view of the amendment to recite “wherein the TRAP protein”.
Claim Rejections - 35 USC § 112(b)
Claims 23, 25-26, 30-34, 36-37, 40 and 46-48 are newly rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The instant rejection is necessitated by claim amendment.
Claim 23 (claims 25-26, 30-34, 36-37 and 40 dependent therefrom) is indefinite for the phrase “providing a TRAP protein with a cysteine residue on the outer perimeter of the TRAP protein at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus”. As there is no recited reference sequence for comparison, the location of the recited mutation in the claimed TRAP protein is unknown.
Claim 46 (claim 47 dependent therefrom) is indefinite for the recitation of “wherein the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a cysteine residue at amino acid position 35”, as it is unclear whether the phrase “with a cysteine residue at amino acid position 35” is intended to limit the claimed TRAP protein at position 35, or whether the phrase is intended to limit the TRAP protein of Geobacillus stearothermophilus. If Applicant is intending to limit the claimed TRAP protein, the location of the cysteine is considered indefinite as there is no recited reference sequence for comparison with which to determine the location of position 35 of the claimed TRAP protein.
Claims 47-48 are indefinite for the recitation of “wherein the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a serine residue at amino acid position 64”, as it is unclear whether the phrase “with a serine residue at amino acid position 64” is intended to limit the claimed TRAP protein at position 64, or whether the phrase is intended to limit the TRAP protein of Geobacillus stearothermophilus. If Applicant is intending to limit the claimed TRAP protein, the location of the cysteine is considered indefinite as there is no recited reference sequence for comparison with which to determine the location of position 64 of the claimed TRAP protein.
Response to Remarks: beginning on p. 7 of Applicant’s response to rejections under 35 USC 112(b); Applicant in summary contends the instant amendments obviate the rejections.
Applicant’s response is considered and found not convincing, as the amendments do not recite any reference sequence from which to determine the location of the mutations of the claimed TRAP protein, as the phrases “corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus” in claim 23 is not a recitation of a reference sequence with which to compare to determine the positions of the recited mutations.
Regarding the rejection of claims 46-48, the amendments to the claims do not obviate the 112(b) rejection, as the phrases “wherein the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a cysteine residue at amino acid position 35” in claim 46 and “wherein the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a serine residue at amino acid position 64” in claims 47-48 are considered indefinite as it is unclear whether the recited residue in each claim is limiting the claimed TRAP protein or is limiting the TRAP protein of Geobacillus stearothermophilus as described above.
.
Claim Rejections - 35 USC § 112(a)
Claim Interpretation: The claims are drawn to a method of conjugating a free thiol group of a moiety of a TRAP protein, comprising
providing a TRAP protein with a cysteine residue on the outer perimeter of the TRAP protein at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus,
contacting the TRAP protein with a gold-donor agent to form a S-Au-S bond, characterized in that the gold-donor agent is halogen(triarylphosphine)gold (I),
wherein the moiety with the free thiol group is the cysteine moiety, and
generating a protein cage biomolecule complex.
According to the instant specification, TRAP proteins are trp RNA binding attenuation proteins from Geobacillus- stearothermophilus [p 1, final paragraph], and according to Bayfield et al. (Plos One, 2012, 7:e44309; cited on the Form PTO-892 mailed 09/04/2024; herein referred to as Bayfield), TRAP proteins are responsible for regulating L-tryptophan biosynthesis in many Bacilli and can be composed of either 11 or 12 subunits depending on the sequence [p 1, col 2, para 2]. As there is no sequence for comparison to determine the location of the cysteine residue of the claimed TRAP protein, the TRAP protein of the independent claim 23 is only limited to have a cysteine residue.
Claims 46-48 limit the claimed TRAP protein to be the TRAP protein of Geobacillus stearothermophilus with either a cysteine at position 35 (claims 46-47) and with a cysteine at position 64 (claims 47-48). As the phrase “with a cysteine” can be interpreted as “comprising a cysteine”, the claimed TRAP protein as recited is not required to have any additional amino acids aside from the residues stated in the claims.
In this case, the genus of recited TRAP proteins encompasses species that are considered to be widely variant with respect to sequence.
A. Claims 23, 25-26, 30-34, 36-37, 40 and 46-48 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed, had possession of the claimed invention.
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
According to MPEP 2163.II.A.3.(a).ii), [s]atisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
The claims recite (in relevant part) a genus of TRAP proteins. As stated above, with the exception of a cysteine residue, the amino acid sequences of the genus of TRAP proteins are unlimited. In this case, the genus of recited TRAP proteins encompasses species that are considered to be widely variant with respect to sequence.
The specification discloses the following representative species of the genus of recited variant polypeptides: The TRAP-CS mutant, which is Geobacillus strearothermophilus TRAP protein, except for K25C and R64S mutations.
The specification does not disclose any additional mutation(s) of the TRAP-CS sequence aside from the K25C and R64S mutations.
Regarding the level of skill and knowledge in the art of amino acid modification, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with residue substitution is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a substitution of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
In view of the high level of unpredictability in the art of amino acid modification, because the genus of TRAP proteins is widely variant with respect to structure, and the specification discloses the actual reduction to practice of only one representative species among a widely variant genus, but without any accompanying amino acid sequence, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the recited genus of TRAP proteins. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
B. Claims 23, 25-26, 30-34, 36-37, 40 and 46-48 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a TRAP protein mutant containing K25C and R64S mutations, does not reasonably provide enablement for all TRAP proteins as encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (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. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
The nature of the invention: According to the specification at p 3, “The subject matter of the invention is a method for conjugation of free thiol group(s) moiety(s) of biomolecules, leading to the biomolecular complex formation, comprising a reaction between biomolecules and gold-donor agent in which -S-Au-S- bond is formed, wherein a gold- donor agent is halogen(triarylphosphine)gold (I). Preferably the biomolecules used in the method are selected from the group comprising peptides, polypeptides, proteins.” The object of the invention is therefore to provide a method for bioconjugation of biomolecules, utilizing thioaurate formation chemistry.
The breadth of the claims: The claims recite (in relevant part) a TRAP protein used in the method for bioconjugation and formation of the -S-Au-S- bond. As stated above, with the exception of a cysteine, the amino acid sequence of the TRAP polypeptide is unlimited.
The state of the prior art; The level of one of ordinary skill; and The level of predictability in the art: According to MPEP 2164.03, “…what is known in the art provides evidence as to the question of predictability” and “[I]f one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art.”
As noted above, the amino acid sequence of the recited polypeptides is unlimited. The reference of Singh (supra) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top).
The unpredictability associated with amino acid modification is exemplified by the reference of Zhang (supra) which discloses that even a mutation that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
While the instant specification discloses a TRAP protein wherein the only identified sequence features are mutations to introduce cysteine [p 9, Example 1], both the instant specification at [p 5, final paragraph] and Heddle et al. (Small, 2007, 11:1950; cited on the Form PTO-892 mailed 09/04/2024) at [p 1951, col 2, para 1] disclose that TRAP proteins lack naturally-occurring cysteine residues that are understood to be required to use the claimed method, indicating that not all TRAP proteins would be able for use in the claimed method without the modification to add a cysteine in the correct location.
As such, one of skill in the art would recognize a high level of unpredictability that all TRAP proteins as encompassed by the claims would be contain the required amino acids to maintain the desired activity/utility.
The amount of direction provided by the inventor and The existence of working examples: The specification discloses the following representative species of the recited TRAP proteins: Geobacillus strearothermophilus TRAP protein, except for K25C and R64S mutations.
The specification does not disclose any additional mutation(s) or amino acids of the TRAP-CS sequence aside from the K25C and R64S mutations and other than this working example, the specification fails to disclose any other TRAP protein.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: While methods of modifying the amino acid sequence of a polypeptide were known at the time of the invention, it was not routine in the art to make and determine a use for all TRAP polypeptides as recited by the claims.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Response to Remarks: beginning on p. 8 of Applicant’s response to 35 U.S.C. 112(a) rejections and p. 1 of Applicant’s declaration under 37 CFR 1.132; Applicant in summary contends that TRAP proteins are essentially identical in terms of structure; Applicant further contends the lysine residue at position 35 is highly conserved among TRAP proteins; Applicant further contends that the structural conservation among TRAP proteins is strong evidence to support that any given TRAP protein comprising the recited cysteine would respond with the same results (e.g., cage formation).
Applicant’s remarks are considered and found not convincing.
While TRAP proteins may share key three-dimensional structural elements, these elements are not defined in the claims or in the specification. Regarding the assertion that all TRAP proteins are essentially identical in structure, in the context of the Examination of claims reciting polypeptides, the structure of a polypeptide encompasses primary structure (e.g., amino acid sequence), and therefore the results of the sequence alignment carried out in the Declaration at para 9 indicating sequence similarity ranging from 36.7% to 100% identity across 3226 results would not be considered to correspond to all TRAP proteins being “essentially identical in structure”.
As claimed, the genus of TRAP proteins comprises polypeptides with undefined amino acid sequences. For example, the phrase recited in claim 23 of “providing a TRAP protein with a cysteine residue on the outer perimeter of the TRAP protein at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus” does not relate the structure of the claimed TRAP protein to any particular protein, as “corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus” instead encompasses all polypeptides from the organism. Therefore, the predictive tools and molecular replacement strategies discussed in the declaration encompass the relation of any and all proteins in the G. stearothermophilus proteome to determine the location of the sole structural element of claimed TRAP protein (e.g., the cysteine), so long as that reference sequence used in the MR shares higher than 35% sequence identity to said protein in G. stearothermophilus.
If Applicant’s intent is to assert that one of skill in the art could make, with a reasonable expectation of success, the TRAP protein of the claims using the tools detailed in the declaration and associated references for use in the claimed method, Applicant should consider an amendment to distinctly identify the reference polypeptide to which the claimed TRAP protein is being compared. As currently amended, obtaining a TRAP protein with cysteine at “at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus” encompasses the alignment of all polypeptides of the organism’s proteome to carry out MR, wherein any created polypeptide sharing >35% identity with a reference polypeptide of the organism’s proteome as encompassed by the claim would be expected to produce a TRAP protein for use in the claimed method. As one of skill in the art would not consider all generated polypeptides by this method to have the recited functional features of the claims, it would be considered undue experimentation to make and use the full scope of the TRAP proteins recited in the claim.
Therefore, the declaration filed 07/30/2025 under 37 CFR 1.132 is fully considered but is not found persuasive for the reasons stated above, and is insufficient to overcome the rejection of claims 23, 25-26, 30, 32-34, 36-37 and 40 under 35 USC 112(a) as set forth in the Office action.
C. Claims 23, 25-26, 30-34, 36-37, 40 and 46-48 are newly rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection and is necessitated by amendment.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims.” See also MPEP 714.02. MPEP § 2163.II.A.3.(b) further states, “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, para. 1, as lacking adequate written description.” According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.”
Claim 23 (claims 225-26, 30-34, 36-37, 40 and 46-48 dependent therefrom) has been amended to recite “providing a TRAP protein with a cysteine residue on the outer perimeter of the TRAP protein at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus”, and
Claims 46-48 have been amended to recite “wherein the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a cysteine residue at amino acid position 35” (claim 46), and “wherein the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a serine residue at amino acid position 64” (claims 47-48).
According to applicant’s instant remarks, “[t]he new claims are fully supported by the application as filed, for example on pages 9-11 and in Fig. 2”. However, there is no apparent descriptive support for the limitations “providing a TRAP protein with a cysteine residue on the outer perimeter of the TRAP protein at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus”, “wherein the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a cysteine residue at amino acid position 35”, and “wherein the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a serine residue at amino acid position 64” in the original application as filed. Absent descriptive support, the noted limitation is considered to introduce new matter into the claims. Applicant is invited to show support for the limitations at issue.
Claim Rejections - 35 USC § 103
Claims 23, 25-26, 30, 32-34, 36-37, 40 and 46-48 are rejected under 35 U.S.C. 103 as being unpatentable over Igashiri-Kamiyama et al. (Dalton Trans, 2011, 40:7249; cited on the IDS filed 05/25/2021; herein referred to as IK), Caddy et al. (Zeitshrift fur Naturforschung B, 2007, 62:460; cited on the IDS submitted 05/25/2021; herein referred to as Caddy), and Heddle et al. (Small, 2007, 11:1950; cited on the Form PTO-892 mailed 09/04/2024; herein referred to as Heddle) and evidentiary reference UniProt Accession No. MTRB_GEOSE (2 pages 11/02/2016; cited on the Form PTO-892 mailed 03/31/2025; herein referred to as UNI).
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Claim 23 is drawn to a method of conjugating a free thiol group of a moiety of a TRAP protein, comprising
(i) providing a TRAP protein with a cysteine residue on the outer perimeter of the TRAP protein at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus,
(ii) contacting the TRAP protein with a gold-donor agent to form a S-Au-S bond, characterized in that the gold-donor agent is halogen(triarylphosphine)gold(I),
wherein the moiety with the free thiol group is the cysteine moiety, and
(iii) generating a protein cage biomolecule complex.
IK discusses the creation of multinuclear and metallosupramolecular compounds from thiol-containing amino acids [title].
Regarding claim 23 and the limitation of conjugating a free thiol group of a moiety of a biomolecule, comprising contacting the biomolecule with a gold-donor agent to form a S-Au-S bond, IK teaches a mononuclear AuI complex [Au(D-pen)2]3- comprising two D-pen ligands bound to an AuI center through thiolato S atoms [abstract, also shown as a reactant in Scheme 1], wherein the D-pen ligands are amino acids bearing free-thiols. IK further discloses the use of such thiolato metal complexes as a metalloligand is of interest in the rational construction of well-organized S-bridged multinuclear structures.
IK does not teach the use of halogen(triarylphosphine)gold (I) donor agents in step (ii), TRAP proteins containing cysteine in step (i), or generating a protein cage in step (iii).
Caddy describes the introduction of phosphine-gold(I) precursors into Cysteine-modified neuropeptides [title], and discusses that gold(I) has a known preference for thiol ligands.
Regarding claim 23 and the limitations in step (ii) of the use of halogen(triarylphosphine)gold (I) donor agents, Caddy teaches chlorine(triphenylphosphine)gold(I) [(Ph3P)AuCl, shown as molecule 1 in Scheme 2] is used as gold donor to form an S-Au linked biomolecule comprising the Ph3P group and a Boc-protected cysteine [shown as molecule 3 in Scheme 2].
Heddle describes using ring-shaped protein TRAP to capture and confine gold nanodots [title], and discusses ring proteins, rather than commonly used spherical protein cages, can be used to constrain gold nanodots via formation of gold-protein complexes [abstract].
Regarding claim 23 and the limitation of a of generating a protein cage biomolecule complex comprising the TRAP proteins that contain cysteine in steps (i) and (iii), Heddle teaches cysteine-bearing mutants of the B. stearothermophilus TRAP protein can be used to provide sulfur atoms for the formation of thioaurate bonds that fix gold nanodots into the central cavity of the TRAP ring [p 1951, col 2, para 1]. The TRAP protein of Heddle is based off of the B. stearothermophilus TRAP [p 1951, col 2, para 1] with the PDB Accession No. 1QAW, which is considered to correspond to UniProt Accession No. MTRB_GEOSE (2 pages 11/02/2016; cited on the attached Form PTO-892; herein referred to as UNI). In view of the lack of a reference sequence for comparison as described in the rejection of the claims under 35 USC 112(b) above, it is unclear where in the claimed TRAP protein the mutations are to occur, and therefore the TRAP protein of Heddle that comprises a cysteine is considered to satisfy the limitation of “a TRAP protein with a cysteine at the outer perimeter of the TRAP protein at the amino acid position corresponding to position 35 in Geobacillus stearothermophilus”.
In view of IK, Heddle and Caddy, it would have been prima facie obvious to one of ordinary skill in the art to modify the method of Caddy by using free thiol-containing amino acids as disclosed by IK that occur in the mutant TRAP protein of Heddle, because Caddy discloses the use of a halogen(triarylphosphine)gold (I) donor agent to form S-Au linked biomolecules, and IK discloses the formation of S-Au-S linked biomolecules, and Heddle discloses the use of cysteine in mutant TRAP proteins used for the formation of thioaurate bonds. One of ordinary skill in the art would have been motivated to modify the method of Caddy because IK teaches the production of thiolato metal complexes is of interest in the rational construction of well-organized S-bridged multinuclear structures, and Heddle teaches cysteine-bearing TRAP protein mutants can function as a protein cage wherein the sulfur atoms of cysteine form a thioaurate bond with gold. One of ordinary skill in the art would have had a reasonable expectation of success because Caddy, IK and Heddle all discuss methods of generating S-Au linked biomolecules.
Regarding claim 25, Heddle teaches the complex of gold nanodot and TRAP protein [p 1951, col 2, para 1], wherein TRAP is comprised of multiple units of the same biomolecule [p 1951, col 1, para 2].
Regarding claim 26, Heddle teaches the mutated TRAP contains symmetry [p 1951, col 1, para 5], wherein one of skill in the art would conclude the complex comprising gold nanodot within the TRAP ring would be symmetrical.
Regarding claims 30 and 32, Caddy teaches the use of the gold donor chlorine(triphenylphosphine)gold(I) [(Ph3P)AuCl, shown as molecule 1 in Scheme 2], which corresponds to the halogen chlorine and a polysubstituted phenyl.
Regarding claim 33, Heddle teaches the immobilization of TRAP-gold complexes on SiO2 followed by the thorough washing with pure water [p 1955, col 2, para 5], corresponding to the purifying of the conjugation product.
Regarding claim 34, Heddle teaches the sequence optimization of the genes encoding TRAP from Bacillus stearothermophilus and subsequent expression in E. coli BL21 (DE3) cells followed by purification via Q-sepharose and HiLoad superdex 200 gel filtration columns [p 1955, col 1, para 2].
Regarding claim 36, Heddle teaches the TRAP adsorption and Au-nanoparticle immobilization on an Si substrate were carried out by a method comprising incubating TRAP in a solution 10 mM Tris-HCl and 50 mM NaCl containing Au-nanoparticles at room temperature for 3 hours [p 1955, col 2, para 2], and Caddy teaches the combination of 0.167 mmol Boc-cysteine (corresponding to the biomolecule) with 0.167 mmol Ph3PAuCl (corresponding to the gold donor) [p 463, col 1, final paragraph], which falls within the claimed range of biomolecule : gold donor ratios of (3 to 1) : (1 to 4).
Regarding claim 37, Heddle teaches the spin drying of the immobilized TRAP-gold complexes on SiO2 [p 1955, col 2, para 5], which encompasses centrifugation.
Regarding claim 40, Heddle teaches the complexation of gold nanodot to mutated TRAP bearing one cysteine [p 1951, col 2, para 1] as discussed in the rejection of claim 23 above, wherein the mutant TRAP contains 12 subunits [p 1951, col 1, para 3], referred to as biomolecule units in the instant application. One of skill in the art would reasonably expect that a gold nanoparticle would react with two of such mutant TRAP proteins as suggested by the IK [as shown by the reactant in Scheme 1], thereby resulting in a protein complex consisting of 24 biomolecule units.
Regarding claims 46-48, in view of indefiniteness of the claims as set forth above, the phrases “the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a cysteine residue at amino acid position 35” in claim 46, and “the TRAP protein is the TRAP protein of Geobacillus stearothermophilus with a serine residue at amino acid position 64” are being interpreted such that recited residues at the recited positions correspond to the claimed TRAP protein. The phrases “with a cysteine residue” in claim 46 and “with a serine residue” in claims 47-48 are being interpreted such that the claimed TRAP protein comprises these residues, and therefore the claimed TRAP protein recited in claims 46-48 is only required to have the residues recited in the claims.
Regarding claim 46, as there is no sequence for reference recited in the claim from which to determine the relative position 35 of the claimed TRAP protein, the TRAP protein of Heddle comprising a cysteine as discussed in the rejection of claim 23 above is considered to be encompassed by the limitations of claim 46.
Regarding claims 47-48, as there is no sequence for reference recited in the claims from which to determine the relative position 64 of the claimed TRAP protein, the TRAP protein of Heddle comprising a serine [see UNI] is considered to be encompassed by the limitations of claims 47-48.
Therefore, the invention of claims 23, 25-26, 30, 32-34, 36-37, 40 and 46-48 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over IK, Caddy, and Heddle as applied to claims 23, 25-26, 30, 32-34, 36-37, 40 and 46-48 above, and further in view of Hamon et al. (ChemComm, 2015, 15:16119; cited on the Form PTO-892 mailed 09/04/2024; herein referred to as Hamon).
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Claim 31 is drawn to the method of claim 23, wherein the gold-donor agent is chloro[diphenyl(3-sulfonatophenyl)phosphine]gold (I).
The teachings of IK, Caddy and Heddle as applied to claims 23, 25-26, 30, 32-34, 36-37, 40 and 46-48 are discussed above. These references do not teach chloro[diphenyl(3-sulfonatophenyl)phosphine]gold (I).
Hamon discusses an aqueous one-pot route to gold/quantum rod heterostructured nanoparticles functionalized with DNA [title], and describes that Au(I) organometallic chemistry provides a versatile approach to controlling surface grafting [abstract].
Regarding claim 31, Hamon teaches the use of the monovalent gold complex chloro-Au(I) known as chloro[diphenyl(3-sulfonatophenyl) phosphine]gold(I) for the conjugation of a heterostructured nanoparticle (HNP) with said gold complex [Scheme 1].
In view of Hamon, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the combined method of Heddle, Caddy and IK by using chloro[diphenyl(3-sulfonatophenyl) phosphine]gold(I), since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that both chloro[diphenyl(3-sulfonatophenyl) phosphine]gold(I) and chlorine(triphenylphosphine)gold(I) are halogen(triarylphosphine)gold(I) molecules used as gold-donor agents for the conjugation of gold-biomolecule complexes, and as such both are capable of being incorporated into methods as described by Heddle, Caddy and IK. Thus it would have been obvious to one of ordinary skill in the art to replace chlorine(triphenylphosphine)gold(I) with chloro[diphenyl(3-sulfonatophenyl) phosphine]gold(I), as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both Caddy and Hamon discuss the use of halogen(triarylphosphine)gold(I) molecules as gold-donor agents.
Therefore, the invention of claim 31 would have been obvious to one of ordinary skill in the art before the effective filing date.
Response to remarks: beginning on p. 14 of Applicant’s response to rejections under 35 USC 103 and p. 7 of Applicant’s Declaration under 37 CFR 1.132 filed 01/03/2025; Applicant in summary contends the claims are amended in scope commensurate with the Applicant’s Declaration under 37 CFR 1.132 filed 01/03/2025 and accordingly the claimed invention would not be obvious over the cited references; Applicant alleges unexpected results in the instant invention that would not have been predictable with the proposed combination of Heddle, IK and Caddy.
Applicant’s response is considered and found not convincing.
Applicant’s allegations of unexpected results correspond to gold (I) atoms linking cysteine between rings rather than resulting in uncontrolled aggregates to form a hyper stable, regular convex polyhedron (i.e., a protein cage) stated in para 22 of the Declaration filed 01/03/2025.
According to MPEP 716.02(b), the burden is on Applicant to explain proffered data. As Applicant has provided no data, Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(b).
According to MPEP 716.02(e), the unexpected results must be compared with the closest prior art. As Applicant has not provided data nor compared with the closest prior art, Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(e).
According to MPEP 716.02(d), unexpected results must be commensurate in scope with the claimed invention. In lieu of providing data, Applicant references the use of gold (I) atoms with cysteine rings to form a stable, regular convex polyhedron, which Applicant asserts to be a protein cage. The claims are drawn to a method for conjugating a free thiol group of a moiety of a TRAP protein, comprising (i) providing a TRAP protein with a cysteine residue on the outer perimeter of the TRAP protein at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus, (ii) contacting the TRAP protein with a gold-donor agent to form a S-Au-S bond, characterized in that the gold-donor agent is halogen(triarylphosphine)gold(I), wherein the moiety with the free thiol group is the cysteine moiety, and (iii) generating a protein cage biomolecule complex. As the claims encompass the conjugation of all TRAP proteins containing cysteine via -S-Au-S- bonds using all halogen(triarylphosphine)gold (I) donor agents, and the claims do not recite the formation of a stable, regular convex polyhedron, or the linking of cysteine rings, Applicant’s allegations of unexpected results are considered not commensurate in scope with the claimed invention, and therefore do not satisfy the requirements of MPEP 716.02(e).
The declaration filed 01/03/2025 under 37 CFR 1.132 is fully considered but is not found persuasive for the reasons stated above, and is found insufficient to rebut a prima facie case of obviousness.
Double Patenting
Claims 23, 25-26, 30, 32-34, 36-37, 40 and 46-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 54 of copending Application No. 18/547,242 (herein “reference application”) in view of IK, Caddy, Heddle and evidentiary reference UNI.
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Regarding instant claim 23, claim 54 of the reference application recites a method of making an artificial TRAP-cage comprising conjugation of the TRAP ring units via at least one free thiol linkage with a cross-linker.
The claims of the reference application do not recite a TRAP protein with a cysteine, contacting the TRAP with a gold-donor agent to form a S-Au-S bond, and the gold-donor agent is halogen(triarylphosphine)gold(I).
IK discusses the creation of multinuclear and metallosupramolecular compounds from thiol-containing amino acids [title].
Regarding instant claim 23 and the limitation of conjugating a free thiol group of a moiety of a biomolecule, comprising contacting the biomolecule with a gold-donor agent to form a S-Au-S bond, IK discloses a mononuclear AuI complex [Au(D-pen)2]3- comprising two D-pen ligands bound to an AuI center through thiolato S atoms [abstract, also shown as a reactant in Scheme 1], wherein the D-pen ligands are amino acids bearing free-thiols. IK further discloses the use of such thiolato metal complexes as a metalloligand is of interest in the rational construction of well-organized S-bridged multinuclear structures.
Caddy describes the introduction of phosphine-gold(I) precursors into Cys-modified neuropeptides [title], and discusses that gold(I) has a known preference for thiol ligands.
Regarding instant claim 23 and the limitation of the use of halogen(triarylphosphine)gold (I) donor agents, Caddy discloses chlorine(triphenylphosphine)gold(I) [(Ph3P)AuCl, shown as molecule 1 in Scheme 2] is used as gold donor to form an S-Au linked biomolecule comprising the Ph3P group and a Boc-protected cysteine [shown as molecule 3 in Scheme 2].
Heddle describes using ring-shaped protein TRAP to capture and confine gold nanodots [title], and discusses ring proteins, rather than commonly used spherical protein cages, can be used to constrain gold nanodots via formation of gold-protein complexes [abstract].
Regarding instant claim 23 and the limitation of a of generating a protein cage biomolecule complex comprising the TRAP proteins that contain cysteine in steps (i) and (iii), Heddle discloses cysteine-bearing mutants of the B. stearothermophilus TRAP protein can be used to provide sulfur atoms for the formation of thioaurate bonds that fix gold nanodots into the central cavity of the TRAP ring [p 1951, col 2, para 1]. The TRAP protein of Heddle is based off of the B. stearothermophilus TRAP [p 1951, col 2, para 1] with the PDB Accession No. 1QAW, which is considered to correspond to UniProt Accession No. MTRB_GEOSE (2 pages 11/02/2016; cited on the attached Form PTO-892; herein referred to as UNI). In view of the lack of a reference sequence for comparison as described in the rejection of the claims under 35 USC 112(b) above, it is unclear where in the claimed TRAP protein the mutations are to occur, and therefore the TRAP protein of Heddle that comprises a cysteine is considered to satisfy the limitation of “a TRAP protein with a cysteine at the outer perimeter of the TRAP protein at the amino acid position corresponding to position 35 in Geobacillus stearothermophilus”.
In view of Heddle, IK and Caddy, it would have been obvious to one of ordinary skill in the art to modify the method of the reference application by using halogen(triarylphosphine)gold (I) donor agents disclosed by Caddy with the free thiol-containing amino acids as disclosed by IK that occur in the mutant TRAP protein of Heddle, because Caddy discloses the use of a halogen(triarylphosphine)gold (I) donor agent to form S-Au linked biomolecules, and IK discloses the formation of S-Au-S linked biomolecules, and Heddle discloses the use of cysteine in mutant TRAP proteins used for the formation of thioaurate bonds. One of ordinary skill in the art would have been motivated to modify the method of the reference application because Caddy discloses gold(I) has a known preference for thiol ligands, IK discloses the production of thiolato metal complexes is of interest in the rational construction of well-organized S-bridged multinuclear structures, and Heddle discloses the mutated TRAP protein can function as a protein cage. One of ordinary skill in the art would have had a reasonable expectation of success because the reference application, Caddy, IK and Heddle all discuss methods of generating thiol-linked biomolecules.
Regarding instant claim 25, Heddle discloses the complex of gold nanodot and TRAP protein [p 1951, col 2, para 1], wherein TRAP is comprised of multiple units of the same biomolecule [p 1951, col 1, para 2].
Regarding instant claim 26, Heddle discloses the mutated TRAP contains symmetry [p 1951, col 1, para 5], wherein one of skill in the art would conclude the complex comprising gold nanodot within the TRAP ring would be symmetrical.
Regarding instant claims 30 and 32, Caddy discloses the use of the gold donor chlorine(triphenylphosphine)gold(I) [(Ph3P)AuCl, shown as molecule 1 in Scheme 2], which corresponds to the halogen chlorine and a polysubstituted phenyl.
Regarding instant claim 33, Heddle discloses the immobilization of TRAP-gold complexes on SiO2 followed by the thorough washing with pure water [p 1955, col 2, para 5], corresponding to the purifying of the conjugation product.
Regarding instant claim 34, Heddle discloses the sequence optimization of the genes encoding TRAP from Bacillus stearothermophilus and subsequent expression in E. coli BL21 (DE3) cells followed by purification via Q-sepharose and HiLoad superdex 200 gel filtration columns [p 1955, col 1, para 2].
Regarding instant claim 36, Heddle discloses the TRAP adsorption and Au-nanoparticle immobilization on an Si substrate were carried out by a method comprising incubating TRAP in a solution 10 mM Tris-HCl and 50 mM NaCl containing Au-nanoparticles at room temperature for 3 hours [p 1955, col 2, para 2], and Caddy discloses the combination of 0.167 mmol Boc-cysteine (corresponding to the biomolecule) with 0.167 mmol Ph3PAuCl (corresponding to the gold donor) [p 463, col 1, final paragraph], which falls within the claimed range of biomolecule : gold donor ratios of (3 to 1) : (1 to 4).
Regarding instant claim 37, for the sake of advancing prosecution, the phrase “comprising at least one of filtration, crystallization, centrifugation, and column chromatography” is being interpreted as “comprising at least one selected from the group consisting of filtration, crystallization, centrifugation, and column chromatography”. Heddle discloses the spin drying of the immobilized TRAP-gold complexes on SiO2 [p 1955, col 2, para 5], which encompasses centrifugation.
Regarding instant claim 40, Heddle discloses the complexation of gold nanodot to mutated TRAP bearing one cysteine [p 1951, col 2, para 1] as discussed in the rejection of claim 23 above, wherein the mutant TRAP contains 12 subunits [p 1951, col 1, para 3], referred to as biomolecule units in the instant application. One of skill in the art would reasonably expect that a gold nanoparticle would react with two of such mutant TRAP proteins as disclosed by the IK [as shown by the reactant in Scheme 1], thereby resulting in a protein complex consisting of 24 biomolecule units.
Regarding instant claim 46, as there is no sequence for reference recited in the claim from which to determine the relative position 35 of the claimed TRAP protein, the TRAP protein of Heddle comprising a cysteine as discussed in the rejection of instant claim 23 above is considered to be encompassed by the limitations of instant claim 46.
Regarding instant claims 47-48, as there is no sequence for reference recited in the claims from which to determine the relative position 64 of the claimed TRAP protein, the TRAP protein of Heddle comprising a serine [see UNI] is considered to be encompassed by the limitations of instant claims 47-48.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 31 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 54 of copending Application No. 18/547,242 in view of IK, Caddy and Heddle as applied to claims 23, 25-26, 30, 32-34, 36-37, 40 and 46-48 above, and further in view of Hamon.
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Claim 31 of the current application is drawn to the method of instant claim 23, wherein the gold-donor agent is chloro[diphenyl(3-sulfonatophenyl)phosphine]gold (I).
The claims of the reference application and the disclosures of IK, Caddy and Heddle as applied to claims 23, 25-26, 30, 32-34, 36-37, 40 and 46-48 are discussed above. The claims of the reference application do not recite chloro[diphenyl(3-sulfonatophenyl)phosphine]gold (I).
Hamon discusses an aqueous one-pot route to gold/quantum rod heterostructured nanoparticles functionalized with DNA [title], and describes that Au(I) organometallic chemistry provides a versatile approach to controlling surface grafting [abstract].
Regarding instant claim 31, Hamon discloses the use of the monovalent gold complex chloro-Au(I) known as chloro[diphenyl(3-sulfonatophenyl) phosphine]gold(I) for the conjugation of a heterostructured nanoparticle (HNP) with said gold complex [Scheme 1].
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the combined method of the reference application, Heddle, Caddy and IK by using chloro[diphenyl(3-sulfonatophenyl) phosphine]gold(I), since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that both chloro[diphenyl(3-sulfonatophenyl) phosphine]gold(I) and chlorine(triphenylphosphine)gold(I) are halogen(triarylphosphine)gold(I) molecules used as gold-donor agents for the conjugation of gold-biomolecule complexes, and as such both are capable of being incorporated into methods as described by the reference application, Heddle, Caddy and IK. Thus it would have been obvious to one of ordinary skill in the art to replace chlorine(triphenylphosphine)gold(I) with chloro[diphenyl(3-sulfonatophenyl) phosphine]gold(I), as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both Caddy and Hamon discuss the use of halogen(triarylphosphine)gold(I) molecules as gold-donor agents.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Remarks: beginning on p. 14 of Applicant’s response to non-statutory double patenting rejections; Applicant in summary contends the claims are not obvious for the reasons discussed in the response to rejections under 35 USC 103.
Applicant’s response is considered and found not convincing. As the response to double patenting rejections is the same as the response to 35 USC 103 rejections, the following section is repeated from above and any changes relate to specifics of co-pending Application 18/547242 (“reference application”).
Applicant’s allegations of unexpected results correspond to gold (I) atoms linking cysteine between rings rather than resulting in uncontrolled aggregates to form a hyper stable, regular convex polyhedron (i.e., a protein cage) stated in para 22 of the Declaration filed 01/03/2025.
According to MPEP 716.02(b), the burden is on Applicant to explain proffered data. As Applicant has provided no data, Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(b).
According to MPEP 716.02(e), the unexpected results must be compared with the closest prior art. As Applicant has not provided data nor compared with the closest prior art, Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(e).
According to MPEP 716.02(d), unexpected results must be commensurate in scope with the claimed invention. In lieu of providing data, Applicant references the use of gold (I) atoms with cysteine rings to form a stable, regular convex polyhedron, which Applicant asserts to be a protein cage. The claims are drawn to a method for conjugating a free thiol group of a moiety of a TRAP protein, comprising (i) providing a TRAP protein with a cysteine residue on the outer perimeter of the TRAP protein at the amino acid position corresponding to the lysine residue at amino acid position 35 in Geobacillus stearothermophilus, (ii) contacting the TRAP protein with a gold-donor agent to form a S-Au-S bond, characterized in that the gold-donor agent is halogen(triarylphosphine)gold(I), wherein the moiety with the free thiol group is the cysteine moiety, and (iii) generating a protein cage biomolecule complex. As the claims encompass the conjugation of all TRAP proteins containing cysteine via -S-Au-S- bonds using all halogen(triarylphosphine)gold (I) donor agents, and the claims do not recite the formation of a stable, regular convex polyhedron, or the linking of cysteine rings, Applicant’s allegations of unexpected results are considered not commensurate in scope with the claimed invention, and therefore do not satisfy the requirements of MPEP 716.02(e).
Therefore the declaration filed 01/03/2025 under 37 CFR 1.132 is fully considered but is not found persuasive for the reasons stated above, and is considered insufficient to overcome the provisional double patenting rejections of record.
Conclusion
Status of the Application:
Claims 23, 25-26, 30-34, 36-37 and 40-48 are pending.
Claims 41-45 are withdrawn.
Claims 23, 25-26, 30-34, 36-37, 40 and 46-48 are rejected.
No claim is in condition for allowance.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656