DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-20 are pending.
Claims 1-20 have been examined on their merits.
Specification
The disclosure is objected to because of the following informalities: the specification references color (see paragraph [0147], reference to “green arrows” in the drawings), but no request for color drawings has been made and approved. Removing reference to color in the drawings would be ameliorative. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8 and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 8 and 17 recites the limitation that targeting molecules “preferentially” bind to target cells. A claim may be rendered indefinite by reference to subjective term (see MPEP 2173.05(b)(IV)). Specifically, the phrase “preferentially” is a subjective term which renders the claim indefinite. The phrase "preferentially" is not defined by the claim, the specification does not provide a standard for some standard for measuring the scope of the term, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970). Claim scope cannot depend solely on the unrestrained, subjective opinion of a particular individual purported to be practicing the invention. Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1350, 75 USPQ2d 1801, 1807 (Fed. Cir. 2005)); see also Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1373, 112 USPQ2d 1188 (Fed. Cir. 2014) (holding the claim phrase "unobtrusive manner" indefinite because the specification did not "provide a reasonably clear and exclusive definition, leaving the facially subjective claim language without an objective boundary”).
For example, in Datamize, the invention was directed to a computer interface screen with an "aesthetically pleasing look and feel." Datamize, 417 F.3d at 1344-45. The meaning of the term "aesthetically pleasing" depended solely on the subjective opinion of the person selecting features to be included on the interface screen. Nothing in the intrinsic evidence (e.g., the specification) provided any guidance as to what design choices would result in an "aesthetically pleasing" look and feel. Id. at 1352. The claims were held indefinite because the interface screen may be "aesthetically pleasing" to one user but not to another. Id. at 1350. See also Ex parte Anderson, 21 USPQ2d 1241 (Bd. Pat. App. & Inter. 1991) (the terms "comparable" and "superior" were held to be indefinite in the context of a limitation relating the characteristics of the claimed material to other materials).
During prosecution, the applicant may overcome a rejection by amending the claim to remove the subjective term, or by providing evidence that the meaning of the term can be ascertained by one of ordinary skill in the art when reading the disclosure. However, "[f]or some facially subjective terms, the definiteness requirement is not satisfied by merely offering examples that satisfy the term within the specification." DDR Holdings, LLC v. Hotels.com, L.P., 773 F.3d 1245, 1261, 113 USPQ2d 1097, 1108 (Fed. Cir. 2014).
For compact prosecution, the term has been interpreted as being optional.
Appropriate clarification is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 8-9, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1).
In regards to claim 1, Rome teaches a vault particle (nanoparticle) for delivery of biomolecule to a subject for therapeutic uses (Abstract; claim 1; paragraph [0126]). Rome teaches that the biomolecule can deliver packaged (thus inside the vault particle, paragraph [0133]) viral vectors (paragraphs [0049, 0070] such as adeno-associated virus (AAV) vectors specifically (paragraphs [0102-0106]).
In regards to part a), Rome teaches that heterologous proteins can be encapsulated inside vault particles using INT protein targeting (paragraph [0006]). A person of ordinary skill in the art would have been motivated to functionalize the capsid of the AAV vector (which is made of protein) in order to encapsulate the virus. Furthermore, because Rome teaches that heterologous proteins (of which an AAV capsid is a type) can be encapsulated using INT protein targeting, it could have been done with predictable results and a reasonable expectation of success.
In regards to part b), Rome teaches that the vault particle comprises MVP proteins (claim 1; paragraphs [0041, 0037]). It is noted that as implies by its name (MVP or major vault protein), it is well known that MVP is the main protein component of vault proteins.
In regards to part c), as above, Rome teaches that heterologous proteins can be encapsulated inside vault particles using INT protein targeting (paragraph [0006]). Continuing, Rome teaches that this results from the INT binding domain on MVP and that in embodiments fusion (i.e., covalent bonding) of proteins to the N-terminus of MVP can be used to localize proteins inside the vault particle (paragraph [0183]). Therefore, a person of ordinary skill in the art would have been motivated to covalently attach an INT moiety near the N-terminus of MVP because it would be effective for encapsulating and localizing proteins (such as the AAV viral capsule) inside the vault particle. Furthermore, because Rome teaches that proteins can be encapsulated and localized by fusing of INT moieties to the N-terminus of MVP, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 8, Rome teaches that in embodiments, vaults can be engineered (functionalized) with targeting molecules for specific cell target binding (paragraphs [0188-0189]).
In regards to claim 9, Rome teaches that a therapeutically effective dose of the composition may be administered to an organism (i.e., treating a patient) (paragraphs [0014-0015, 0061, 0112-00129]).
In regards to the composition itself, as above, Rome teaches a vault particle for delivery of biomolecule to a subject for therapeutic uses (Abstract; claim 1; paragraph [0126]). Rome teaches that the biomolecule can deliver packaged (thus inside the vault particle, paragraph [0133]) viral vectors (paragraphs [0049, 0070] such as adeno-associated virus (AAV) vectors specifically (paragraphs [0102-0106]).
In regards to part a), Rome teaches that heterologous proteins can be encapsulated inside vault particles using INT protein targeting (paragraph [0006]). A person of ordinary skill in the art would have been motivated to functionalize the capsid of the AAV vector (which is made of protein) in order to encapsulate the virus. Furthermore, because Rome teaches that heterologous proteins (of which an AAV capsid is a type) can be encapsulated using INT protein targeting, it could have been done with predictable results and a reasonable expectation of success.
In regards to part b), Rome teaches that the vault particle comprises MVP proteins (claim 1; paragraphs [0041, 0037]). It is noted that as implies by its name (MVP or major vault protein), it is well known that MVP is the main protein component of vault proteins.
In regards to part c), as above, Rome teaches that heterologous proteins can be encapsulated inside vault particles using INT protein targeting (paragraph [0006]). Continuing, Rome teaches that this results from the INT binding domain on MVP and that in embodiments fusion (i.e., covalent bonding) of proteins to the N-terminus of MVP can be used to localize proteins inside the vault particle (paragraph [0183]). Therefore, a person of ordinary skill in the art would have been motivated to covalently attach an INT moiety near the N-terminus of MVP because it would be effective for encapsulating and localizing proteins (such as the AAV viral capsule) inside the vault particle. Furthermore, because Rome teaches that proteins can be encapsulated and localized by fusing of INT moieties to the N-terminus of MVP, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 16, it is noted that the claim does not require any specific configuration for “prevent the AAV vector from a neutralizing antibody produced by an immune response to the AAV therapy.” Indeed, the specification states that the vault/AAV complex (VAAV) itself has this property (instant paragraphs [0148-0152], specifically, “These data demonstrate that VAAV protects its AAV cargo from neutralizing serum as well as enhances cellular transduction, allowing for the delivery of AAV gene therapy despite neutralizing antibodies” (paragraph [0148]). Thus, this is a property of the vault/AAV complex.
According to MPEP 2112, “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that “just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.” Id.
Moreover, there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
In the instant case since Rome teaches a vault/AAV complex, and since the specification indicates that the vault/AAV complex itself is configured to prevent neutralization by antibodies, the composition of Rome would have this property absent evidence to the contrary.
In regards to claim 17, Rome teaches that in embodiments, vaults can be engineered (functionalized) with targeting molecules for specific cell target binding (paragraphs [0188-0189]).
Therefore, the teachings of Rome render the invention unpatentable as claimed.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1) as applied to claim 1 above, and further in view of Hatlem et al. (International Journal of Molecular Science, 2019).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1) as applied to claim 9 above, and further in view of Hatlem et al. (International Journal of Molecular Science, 2019).
In regards to claims 2 and 10, Rome does not explicitly teach that the AAV protein capsid comprises a pluralities of SpyTag/SpyCatcher proteins, etc. as in claim 2.
However, the SpyCatcher-SpyTag system is a long-known protein ligation system. As taught by Hatlem, capsids surfaces can comprise a plurality of SpyTag proteins covalently attached to pluralities of SpyCatcher proteins which themselves are covalently attached to proteins of interest (e.g., INT as above) (Fig. 2, p5). A person of ordinary skill in the art would have been motivated to utilize the SpyCatcher-SpyTag because Hatlem teaches that it is a quick and reliable coupling tool for irreversible peptide-protein ligation, and is ideal for a wide range of applications including increased protein stability and specifically for the encapsulation of enzymes fused to phage capsid proteins in order to create a protein nanocompartment (Applications of the SpyCatcher-SpyTag System, p4; Fig. 2, p5). Furthermore, because Hatlem teaches that SpyCatcher-SpyTag system can be used to encapsulate vectors it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Rome and Hatlem render the invention unpatentable as claimed.
Claims 3 and 6-7 is rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1) and Hatlem et al. (International Journal of Molecular Science, 2019) as applied to claims 1 or 2 above, and further in view of Keeble et al. (Chemical Science, 2020).
Claims 11 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1) and Hatlem et al. (International Journal of Molecular Science, 2019) as applied to claims 9 or 10 above, and further in view of Keeble et al. (Chemical Science, 2020).
In regards to claims 3 and 11, Rome as modified by Hatlem are silent as to the specific SpyCatcher/SpyTag used. However, a person of ordinary skill in the art would have been motivated to use SpyCatcher003 and SpyTag003 because Keeble teaches has kinetics approaching infinite affinity and creates more product in a shorter amount of time compared to other variants (Infinite affinity: concept, engineering and potential, p7281-7282; Fig. 1, p7282). Furthermore, because SpyCatcher003 and SpyTag003 are known SpyCatcher/SpyTag variants for ligating proteins, it could have been done with predicable results and a reasonable expectation of success.
In regards to claims 6-7 and 14-15, Rome teaches that AAV vector may comprise for genes for treating cells (i.e., therapeutic genes) (paragraph [0106]). Furthermore, the compositions/methods of Rome are all in the context of treating delivering fusions proteins to tissues for gene therapy (paragraphs [0103-0104]). Therefore, it would have been predicably obvious to select a gene from a gene therapy for a genetic disease.
Therefore, the combined teachings of Rome, Hatlem, and Keeble render the invention unpatentable as claimed.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1), Hatlem et al. (International Journal of Molecular Science, 2019), and Keeble et al. (Chemical Science, 2020) as applied to claims 1-3 above, and further in view of Chen et al. (Advanced Drug Delivery Reviews, 2013) and Schroeder et al. (US2009307791).
Claims 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1), Hatlem et al. (International Journal of Molecular Science, 2019), and Keeble et al. (Chemical Science, 2020) as applied to claims 9-11 above, and further in view of Chen et al. (Advanced Drug Delivery Reviews, 2013) and Schroeder et al. (US2009307791).
In regards to claims 4-5 and 12-13, it is noted that the flanking sequences AGGGSGGS are “GS linkers” as referred to in the art. A person of ordinary skill in the art would have been motivated to include GS linkers because for recombinant proteins, they provide flexibility and increase spatial separation between domains as taught by Chen (Table 2, p1360; Flexible linkers, p1359-1360). In regards to the alanine, a person of ordinary skill in the art would have been motivated to include this amino acid because Chen teaches that GS linkers can be modified to contain an additional alanine in order to maintain flexibility (Flexible linkers, p1359-1360). They would have been motivated to add additional linkers (such as a second flanking linker or a third linker) in order to order to optimize appropriate separation of functional domains (see Chen, Flexible linkers, p1359-1360; see also MPEP 2144.04(VI)(B), the mere duplication of parts has no patentable significance unless a new and unexpected result is produced. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960)). Furthermore, because Chen teaches that it is known in the art that GS linkers including those modified with an alanine are readily used in engineering recombinant proteins (Abstract, p 1357; Flexible linkers, p1359-1360) and because as taught by Schroeder the sequence AGGGSGGS is a known linker (paragraphs [0018, 0098]; SEQ ID NO: 11; see Rag file. us-18-775-975a-4.rag on 07/02/2026), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Rome, Hatlem, Keeble, Chen, and Schroeder render the invention unpatentable as claimed.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1) in view of Hatlem et al. (International Journal of Molecular Science, 2019) and Chen et al. (Advanced Drug Delivery Reviews, 2013).
In regards to claim 18, Rome teaches methods for encapsulating (i.e., providing) compositions of biomolecules inside vault nano particles (nanoparticles) (Abstract; claim 1; paragraphs [0038, 0126, 0138]).
Rome teaches that the biomolecule can deliver packaged (thus inside the vault particle, paragraph [0133]) viral vectors (paragraphs [0049, 0070] such as adeno-associated virus (AAV) vectors specifically (paragraphs [0102-0106]).
In regards to steps a) through e), Rome teaches that heterologous proteins can be encapsulated inside vault particles using (thus providing) INT protein targeting (paragraph [0006]). Rome teaches that this results from INT (with covalently bound fusion proteins) binding to MVP inside the vault particle (paragraph [0183]).
While Rome teaches Rome does not explicitly teach that the AAV protein capsid and INT proteins comprise a pluralities of SpyTag/SpyCatcher proteins, etc., as taught by Hatlem, capsids surfaces can comprise a plurality of SpyTag proteins covalently attached to pluralities of SpyCatcher proteins which themselves are covalently attached to proteins of interest (e.g., INT as above) (Fig. 2, p5). A person of ordinary skill in the art would have been motivated to utilize (and therefore, provide) SpyCatcher-SpyTag because Hatlem teaches that it is a quick and reliable coupling tool for irreversible peptide-protein ligation, and is ideal for a wide range of applications including increased protein stability and specifically for the encapsulation of enzymes fused to phage capsid proteins in order to create a protein nanocompartment (Applications of the SpyCatcher-SpyTag System, p4; Fig. 2, p5). Furthermore, because Hatlem teaches that SpyCatcher-SpyTag system can be used to encapsulate vectors and because Rome teaches that INT-mediated encapsulation is a method for encapsulating heterologous proteins, it could have been done with predictable results and a reasonable expectation of success.
In regards to the arrangement of linkers for the capsid and INT proteins, a person of ordinary skill in the art would have been motivated to include linkers (such as flexible GS linkers) because for recombinant proteins, they provide flexibility and increase spatial separation between domains as taught by Chen (Table 2, p1360; Flexible linkers, p1359-1360). They would have been motivated to add additional linkers (such as a second flanking linker or a third linker) in order to order to optimize appropriate separation of functional domains (see Chen, Flexible linkers, p1359-1360; see also MPEP 2144.04(VI)(B), the mere duplication of parts has no patentable significance unless a new and unexpected result is produced. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960)). Furthermore, because Chen teaches that it is known in the art that linkers including GS linkers are readily used for engineering recombinant proteins (Abstract, p 1357; Flexible linkers, p1359-1360), it could have been done with predictable results and a reasonable expectation of success.
In regards to the active method steps, Rome teaches that the composition is prepared by mixing a fusion protein with an MVP protein for a sufficient amount of time (thus, incubating) to allow packaging of the fusion protein inside the vault complex (paragraph [0138]). Rome also teaches that the use of examples is for illustrative purposes only and does not limit the scope and meaning of the embodiments of the invention herein (paragraph [0038]), and therefore, since packaging AAVs is an embodiment as taught by Rome, a person of ordinary skill in the art would have recognized that encapsulating those AAVs by incubating them with MVPs for a sufficient amount of time to allow their packaging was also an embodiment as suggested by Rome.
Therefore, the combined teachings of Rome, Hatlem, and Chen renders the invention unpatentable as claimed.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1) in view of Hatlem et al. (International Journal of Molecular Science, 2019) and Chen et al. (Advanced Drug Delivery Reviews, 2013) as applied to claim 18 above, and further in view of Lai et al. (ACS Nano, 2009).
In regards to claim 19, step a) requires mixing AAV vectors with fusion proteins (e.g., SpyTag) at a 1 to 10 ratio. Since SpyCatcher binds to SpyTag, step a) also implies that the ratio of AAV vector to INT-SpyCatcher is also 1 to 10. Step b) requires mixing INT-functionalized AAV vectors (e.g., INT bound to SpyCatcher which then bind to SpyTag as in step a)) to vault nanoparticles at a ratio of 1 to 5.
While, Rome teaches that in embodiments dye mixed with vaults resulting in a 1:1 ratio (paragraph [0155]), and is therefore, silent as to the specific ratios as in steps a) and b), a person of ordinary skill in the art could have arrived at the claimed ratios by routine optimization with predictable results and a reasonable expectation of success, and importantly, the disclosure does not point to a criticality in these ratios.
In regards to routine optimization, MPEP 2144.05(II)(A) states differences in concentration (here, the ratios of AAV vectors to fusion proteins or AAV vectors to vault nanoparticles) will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.).
Again, as above, the disclosure does not demonstrate a criticality at the claimed ratios.
Furthermore, as taught by Lai, “Based on densitometric analysis of coomassie stained SDS-PAGE, we estimate that on average, each vault particle contains 20-30 molecules of the pVI-INT protein. This number is consistent with packaging of multiple copies of other INT fusion proteins into recombinant vaults. Gas-phase electrophoretic mobility molecular analysis (GEMMA) indicate that INT fusion proteins are packaged into all vaults (as the entire vault population shifts to a higher molecular mass). With an estimate of 20-30 pVI INT proteins per vault it is likely that this is at or near a saturating level for this size protein suggesting that it is unlikely that there are any empty vaults in the population” (p2-3). It is noted that Lai and Rome are both co-authors/inventors of the cited prior art. Thus, as taught by Lai, packing of vault to their saturation levels (thus, the required ratios of vaults and biomolecules (such as AAV vectors) to fit in them) is a function of the size of the protein (the vectors and fusion proteins).
Therefore, because Rome teaches that molecules can at least be packed in vaults at a ratio of 1:1 and because Lai (which is the same inventive entity of Rome) teaches that packing is a function of protein size, a person of ordinary skill could have arrived at the ratios as in claim 19 by routine optimization with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Rome, Hatlem, Chen, and Lai render the invention unpatentable as claimed.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Rome et al. (US20110201112A1) in view of Hatlem et al. (International Journal of Molecular Science, 2019) and Chen et al. (Advanced Drug Delivery Reviews, 2013) as applied to claim 18 above, and further in view of Keeble et al. (Chemical Science, 2020) and Schroeder et al. (US2009307791).
In regards to claim 20, a person of ordinary skill in the art would have been motivated to use SpyCatcher003 and SpyTag003 because Keeble teaches has kinetics approaching infinite affinity and creates more product in a shorter amount of time compared to other variants (Infinite affinity: concept, engineering and potential, p7281-7282; Fig. 1, p7282). Furthermore, because SpyCatcher003 and SpyTag003 are known SpyCatcher/SpyTag variants for ligating proteins, it could have been done with predicable results and a reasonable expectation of success.
In regards to the sequences of the linkers, a person of ordinary skill in the art would have been motivated to include GS linkers because for recombinant proteins, they provide flexibility and increase spatial separation between domains as taught by Chen (Table 2, p1360; Flexible linkers, p1359-1360). In regards to the alanine, a person of ordinary skill in the art would have been motivated to include this amino acid because Chen teaches that GS linkers can be modified to contain an additional alanine in order to maintain flexibility (Flexible linkers, p1359-1360). They would have been motivated to add additional linkers (such as a second flanking linker or a third linker) in order to order to optimize appropriate separation of functional domains (see Chen, Flexible linkers, p1359-1360; see also MPEP 2144.04(VI)(B), the mere duplication of parts has no patentable significance unless a new and unexpected result is produced. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960)). Furthermore, because Chen teaches that it is known in the art that GS linkers including those modified with an alanine are readily used in engineering recombinant proteins (Abstract, p 1357; Flexible linkers, p1359-1360) and because as taught by Schroeder the sequence AGGGSGGS is a known linker (paragraphs [0018, 0098]; SEQ ID NO: 11; see Rag file. us-18-775-975a-4.rag on 07/02/2026), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Rome, Hatlem, Chen, Keeble, and Schroeder render the invention unpatentable as claimed.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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