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 H. Maynard et al., US 18/366,766 (Mar. 29, 2021) are pending. Claims 11-21 drawn to non-elected Groups (II)-(III) are withdrawn from consideration pursuant to 37 CFR 1.142(b). Claims 1-10 are under examination on the merits. Claim 1-10 are rejected.
Election/Restrictions
Pursuant to the restriction requirement, Applicant elected Claims 1-10, without traverse, drawn to a composition comprising a polypeptide having at least one cysteine residue and a gold(III) aryl complex, the gold(III) aryl complex comprising a polyethylene glycol group, in the response filed on January 27, 2026. Claims 11-21 drawn to non-elected Groups (II)-(III) are withdrawn from consideration pursuant to 37 CFR 1.142(b). The restriction requirement is made FINAL
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 H. Montgomery et al., 33 Bioconjugate Chemistry, 1536-1542 (published August 8, 2022) (“Montgomery”)
Prior Art Effect of Montgomery
Montgomery is effective prior art under 35 USC § 102(a)(1) because it was published on August 8, 2022, less than one year before the instant presumed effective filing date of June 16, 2023. Montgomery names the additional author “Hayden R. Montgomery” over the instant inventorship. In view of the common authors/inventors, Applicant may consider an exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection by a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1). MPEP § 717(I)/(III). For example, if Montgomery’s additional inventor “Hayden R. Montgomery” is the same person as the instantly named inventor “Hayden Montgomery Aytac” then it would be clear that Montgomery’s disclosure, is by one or more joint inventor(s) and does not name anyone else. MPEP § 717.01(III).
The Claim 1 “composition”
Claim 1 recites as follows:
1. A composition comprising a polypeptide having at least one cysteine residue and a gold(III) aryl complex, the gold(III) aryl complex comprising a polyethylene glycol group having an average molecular weight greater than 1 kDa attached to the aryl group.
The claim 1 “composition” clearly requires at least two separate chemical entities as a mixture: (1) a polypeptide having at least one residue having a free thiol (e.g., cysteine); and (2) a gold(III) aryl complex. Specification at page 5, lines 9-27; MPEP § 2111. The specification teaches that the purpose of forming the claim 1 composition is so that the a gold(III) aryl complex comprising a polyethylene glycol group reacts with the polypeptide so as to form a cysteine-aryl conjugated polypeptide. Specification at paragraph bridging pages 8-9; see also, Fig. 3. Thus, the specification’s disclosed purpose for the composition is its function as a reaction mixture. The specification teaches that such conjugation of polypeptides to PEG significantly increases both stability and in vivo lifetime, making the application of proteins and peptides as disease treatments more feasible and effective. Specification at page 1, lines 18-26.
The § 102 Rejection
Claims 1-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by H. Montgomery et al., 33 Bioconjugate Chemistry, 1536-1542 (published August 8, 2022) (“Montgomery”).
Montgomery teaches that reaction of 2, 5, and 10 kDa mPEG-Au(III) reagents with a cysteine thiol on a biomolecule resulted in facile and selective cysteine arylation chemistry, forging covalent S-aryl linkages and affording the mPEG-biomolecule conjugates. Montgomery at Abstract. Montgomery teaches preparation of mPEG-biomolecule conjugate by reacting poly(ethylene glycol) monomethyl ether (mPEG)-Au(III)-(Me-DalPhos) reagents with proteins and peptides containing cysteine.
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Montgomery at page 1538, col. 1 (referencing Figure 1b). In the working examples, Montgomery teaches a composition of each of 2, 5, and 10 kDa mPEG-Au(III) (which is “gold(III) aryl complex comprising a polyethylene glycol group having an average molecular weight greater than 1 kDa attached to the aryl group”) and DARPin (which is “a polypeptide having at least one cysteine residue”). Montgomery at page 1539, col. 1; See also, Id. at page S29 (5kDa Au(III) PEG—DARPin conjugates); S30 (10 kDa Au(III) PEG—DARPin conjugates). Montgomery therefore clearly meets each and every limitation of claims 1-2.
Respecting claims 3 and 4, Montgomery teaches
Au(III) equivalent conjugation screen: (70 μM DARPin, pH 7.5, 4 equiv. TCEP, X equiv. Au(III), 1 minute, 25 °C) To 50 μL of a solution of 76 μM DARPin in 20 mM Tris, 150 mM NaCl buffer, pH 7.5, was added 5 μL of a 3 mM stock solution of TCEP•HCl (4 equivalents) in MilliQ H2O. This was allowed to sit at 25 °C for one hour to reduce any disulfide bonds formed during storage. Then, 5 μL of a 0.76, 0.9, 1.2 or 1.5 mM stock solution of Au(III) mPEG (1, 1.2, 1.5 or 2 equivalents, respectively) reagent was added, gently flicked to mix and allowed to react for one minute.
Montgomery at page S30. The molar rations of claims 3 and 4 are therefore clearly met by Montgomery.
The limitations of claim 5 is met because designed ankyrin repeat proteins (DARPins) have a molecular weight of approximately 15 kDa. M. Altai et al., 10 EJNMMI Research, 1-8, (2020) (page 1).
The limitations of claim 6 are clearly met because Montgomery’s 2, 5, and 10 kDa mPEG-Au(III) are the same as those claimed.
The limitations of claim 7 are met because Montgomery’s composition of 2, 5, and 10 kDa mPEG-Au(III) and DARPin comprises “one or more of a reducing agent, a buffer, a salt, and solvent”. Per the above experimental excerpt Montgomery’s composition comprises “20 mM Tris, 150 mM NaCl buffer”. Montgomery at page S30.
The limitations of claim 8 are met because Montgomery’s composition of 2, 5, and 10 kDa mPEG-Au(III) and DARPin has a pH of between 5.5 and 7.5. Montgomery at page 1539, Table 1.
Claim 9 recites:
9. The composition of claim 1, wherein the composition comprises more than 50 μM of the polypeptide.
In the chemical arts molarity or moles per liter is indicated by a capital M. Claim 9 therefore literally reads as ‘comprises more than 50 μmols polypeptide per liter of the composition’. See e.g., Hawley's Condensed Chemical Dictionary, page 944 (16th ed., 2016, R.J. Larrañaga ed.). Per the above experimental excerpt, Montgomery’s composition comprises 70 μM DARPin in the buffered reaction medium and therefore meets the molarity limitations of claim 9. Montgomery at page S30.
The limitations of claim 10 are met because, per the above experimental excerpt, Montgomery’s composition of 2, 5, and 10 kDa mPEG-Au(III) and DARPin reacts to form a PEG-aryl-DARPin conjugate, which corresponds to the claim 10 “cysteine-aryl conjugated polypeptide”. Montgomery at page S30. In other words, at some time point after mixing the 2, 5, and 10 kDa mPEG-Au(III) and DARPin, the PEG-aryl-DARPin conjugate will also be present; at least until and if the mPEG-Au(III) and DARPin are completely reacted. Thus, all three required claim 10 components are present in Montgomery’s composition.
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 1-10 are rejected under AIA 35 U.S.C. 103 as being unpatentable over M. Messina et al., 140 Journal of the American Chemical Society, 7065-7069 (2018) (“Messina”) in view of F. Veronese et al., 22 Biodrugs, 315-319 (2008) (“Veronese”); J. Harris et al., 2 Nature Review Drug Discovery, 241-221 (2003) (“Harris) and A. Wijesinghe et al., PLOS ONE, 1-19 (2022) (“Wijesinghe”).
M. Messina et al., 140 Journal of the American Chemical Society, 7065-7069 (2018) (“Messina”)
Messina teaches an efficient method for chemoselective cysteine arylation of unprotected peptides and proteins using Au(III) organometallic complexes. Messina at Abstract.
Messina teaches the following general equation for C−S bond formation in the disclosed cysteine arylation processes.
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Messina at page 7065, col. 2. Messina teaches pegylated gold complex 2o (see structural depiction of 2o below). Messina at page 7066, col. 2, Fig. 2. Messina teaches that under the optimized bioconjugation conditions (25 °C, 3 equiv Au complex, 80:20 H2O : MeCN, 0.1 M Tris buffer, pH 8.0), a quantitative conversion to the GSH S-aryl conjugates was observed for substrate 2o in <5 min. Messina at page 7066, col. 2, last paragraph. In the supplementary materials, Messina teaches the corresponding experimental for cysteine arylation using pegylated gold complex 2o.
Cysteine arylation using compound 2o: To a 2 mL Eppendorf tube was added 50 μL of peptide stock solution in 200 mM Tris pH 8.0. To this solution was added 50 μL of a 6 mM gold reagent stock solution in water (MilliQ), and the Eppendorf tube was vortexed (<5 seconds). At one min, a 20 μL aliquot was removed and diluted in a 100 μL solution of 1:1 H2O:MeCN with 0.1% mol TFA. An aliquot from this solution was analyzed via LCMS.
Messina at page S129.
The Examiner summarizes Messina’s cysteine arylation of tripeptide glutathione (i.e., Glu-Cys-Gly)1, using substrate 2o, as follows:
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Messina at page 7066, col. 2, last paragraph; Id. at page S129. Messina further teaches di-pegylation of the two accessible cysteine residues of fibroblast growth factor 2 FGF2 using 2o. Messina at page S139, Figure S102. Fibroblast growth factor 2 (FGF-2) is a small 18 kDa protein with clinical potential for ischemic heart disease, wound healing, and spinal cord injury. T. Lühmann et al., 6 ACS Biomaterials Science & Engineering, 425-432 (2020).
Differences between Messina and Claim 1
Messina teaches (per claim 1) a composition (i.e., a reaction mixture) comprising a polypeptide having at least one cysteine residue and a gold(III) aryl complex, the gold(III) aryl complex comprising a polyethylene glycol group.
Messina differs from claim 1 only in that the polyethylene glycol (PEG) group of the gold (III) aryl complex 2o has a molecular weight of 0.550 kDa, whereas claim 1 requires a PEG “having an average molecular weight greater than 1 kDa”.
F. Veronese et al., 22 Biodrugs, 315-319 (2008) (“Veronese”)
As summarized below, Veronese teaches that for PEGylated proteins and peptides, the molecular weight of the polyethylene glycol chain is a result-effective variable, where PEG molecular weights in the range of 5 to 50 kDa generally being employed in FDA approved conjugates.
Veronese teaches that the precise structure of peptides allows them to play important roles as activators or inhibitors of biological mechanisms, or as biocatalysts in metabolic processes are therefore an obvious choice as new therapeutic agents. Veronese at page 315, col. 1. Veronese teaches that the intrinsic properties of these macromolecules, however, present drawbacks that limit their administration, such as instability, degradation by proteolytic enzymes, rapid excretion, and potential immunogenicity. Veronese at page 315, col. 1. Veronese teaches that PEG conjugation to peptides improves solubility, and the conjugates become resistant to antibodies, proteolytic enzymes and cells, and, because of their increased size (figure 1), are ultra-filtered by the kidneys more slowly. Veronese at page 315, col. 2.
Veronese teaches that cysteine thiol residues, when present, are also very convenient because, being seldom present in proteins, they allow site-specific conjugation; furthermore, they can be conveniently introduced by genetic engineering at desired sites in the sequence. Veronese at page 316, col. 2.
Veronese teaches a listing of PEGylated proteins or oligonucleotides approved by the US FDA, where the molecular weight range of the PEG is 5 kDa – 40 kDa. Veronese at page 318, Table II. Veronese teaches that the size of the polymer plays a significant role in determining the biological behavior of PEG conjugates. Veronese at page 320, col. 2. Veronese teaches that the mass of bound PEG is important for determining the time it remains in the blood and the required mass can be reached by adding either several small PEG chains to the protein, or alternatively one PEG chain of high mass. Veronese at page 320, col. 2. Veronese teaches that pharmaceutical grade PEG should have a polydispersity spanning from 1.01 for a product of 5 kDa, up to 1.1 for a product of 50 kDa. Veronese at page 320, col. 2.
J. Harris et al., 2 Nature Review Drug Discovery, 241-221 (2003) (“Harris)
Harris provides similar teaches to Veronese. Harris teaches pegylating site-specifically can minimize the loss of biological activity and reduce immunogenicity. Harris at page 216, col. 2. Harris teaches that because there are far fewer cysteine residues than lysine groups on polypeptides, the THIOL groups of cysteine are ideal for specific modifications and moreover, cysteines can be added to polypeptides precisely where they are desired by genetic engineering. Harris at page 216, col. 2.
A. Wijesinghe et al., PLOS ONE, 1-19 (2022) (“Wijesinghe”)
Wijesinghe teaches that while peptides can be excellent therapeutics for several conditions, their limited in vivo half-lives have been a major bottleneck in the development of therapeutic peptides. Conjugating the peptide to an inert chemical moiety is a strategy that has repeatedly proven to be successful in extending the half-life of some therapeutics. Wijesinghe at Abstract.
Wijesinghe teaches that therapeutic molecules that are smaller than the threshold for renal filtration, which is thought to be ~70 kDa, are more likely to undergo faster renal clearance as compared to those that are larger. Wijesinghe at page 3, 1st full paragraph.
Wijesinghe teaches that in the search for conjugates with favorable characteristics, researchers have observed that attaching moieties capable of increasing the peptide’s size and/or altering its charge has potential to successfully extend plasma half-life. Attaching a conjugate that is relatively large like PEG can increase the MW of the peptide by 2–40 kDa allowing it to evade kidney filtration. Wijesinghe at paragraph bridging pages 3-4.
Obviousness Rationale
Claim 1 is obvious because one of ordinary skill seeking to therapeutically employ and improve the pharmacokinetics of a cysteine-containing polypeptide is motivated to prepare a composition, comprising Messina’s gold (II) aryl complex 2o, but where 2o’s polyethylene glycol group is extended from n=10 to an average molecular weight greater than 2 kDa, in order to conjugate the polyethylene glycol group to the polypeptide as follows:
Proposed Modification of Messina (employ higher molecular weight PEG)
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One of ordinary skill is motivated to employ 2o (modified by PEG extension to greater than 2kDa) because Veronese, Harris and Wijesinghe teach that PEG conjugation improves peptide pharmacokinetics and that PEG molecular weights in the range of 5 kDa - 40 kDa represents an optimized pharmacokinetic range for pharmacokinetic/therapeutic efficacy. For example, Veronese teaches a listing of PEGylated proteins or oligonucleotides approved by the US FDA, where the molecular weight range of the PEG is 5 kDa – 40 kDa. Veronese at page 318, Table II. In another example, Wijesinghe teaches that attaching a conjugate that is relatively large like PEG can increase the MW of the peptide by 2–40 kDa allowing it to evade kidney filtration. Wijesinghe at paragraph bridging pages 3-4.2
One of ordinary skill has a reasonable expectation of success, because Messina teaches that a comprehensive demonstration of the aryl scope was performed with GSH under the optimized bioconjugation conditions (25 °C, 3 equiv. Au complex, 80:20 H2O:MeCN, 0.1 M Tris buffer, pH 8.0) and quantitative conversion to the GSH S-aryl conjugates was observed in <5 min for all 17 substrates displayed in Figure 2A (b−r), indicating to one of ordinary skill that the reaction is facile and general for cysteine-containing peptides. Messina at page 7066, col. 2. Still further, Messina teaches di-pegylation of the two accessible cysteine residues of fibroblast growth factor 2 (FGF2) using 2o. Messina at page S139, Figure S102. Claims 1 and 2 are obvious over the cited art.
Respecting claims 3 and 4, In the supplementary materials, Messina teaches the corresponding experimental for cysteine arylation using pegylated gold complex 2o.
Cysteine arylation using compound 2o: To a 2 mL Eppendorf tube was added 50 μL of peptide stock solution in 200 mM Tris pH 8.0. To this solution was added 50 μL of a 6 mM gold reagent stock solution in water (MilliQ), and the Eppendorf tube was vortexed (<5 seconds). At one min, a 20 μL aliquot was removed and diluted in a 100 μL solution of 1:1 H2O:MeCN with 0.1% mol TFA. An aliquot from this solution was analyzed via LCMS.
Messina at page S129. Messina’s above-employed 50 μL of peptide stock solution is 2 mM glutathione. Messina at page S109, lines 7-8. Thus, the above composition (total volume 300 μL) contains 0.1 μmol of peptide and 0.3 μmol of gold complex. The molar ratio of gold (III) aryl complex to the peptide in the Messina composition is therefore 3 (which falls within the claim 3 concentration range, but outside the claim 4 concentration range), and which would be starting point for routine optimization.3 Here, claims 3 and 4 are obvious because one or ordinary skill is motivated to adjust the molar ratio of gold (III) aryl complex to polypeptide depending on the peptide employed (e.g., the number of available cysteine residues). Further, Messina’s molar ratio of 3 falls within the claim 3 range and is close to the claim 4 range of “between 1 and 2”. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. MPEP § 2144.05(I). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Id.
Claim 5 is obvious because numerous therapeutic polypeptides considerable for conjugation have a molecular weight greater than 10kDa. For example, Messina teaches di-pegylation of the two accessible cysteine residues of fibroblast growth factor 2 (FGF2) using 2o. Messina at page S139, Figure S102. Fibroblast growth factor 2 (FGF-2) is a small 18 kDa protein with clinical potential for ischemic heart disease, wound healing, and spinal cord injury. T. Lühmann et al., 6 ACS Biomaterials Science & Engineering, 425-432 (2020).
The limitations of claim 6 are clearly met because the proposed mPEG-Au(III) complex is the same as that claimed.
The limitations of claim 7 are met because Messina’s composition comprises “one or more of a reducing agent, a buffer, a salt, and solvent”. Per the above experimental excerpt Messina’s composition comprises “50 μL of peptide stock solution in 200 mM Tris pH 8.0”. Messina at page S129.
Respecting claim 8, Messina teaches a pH of 8, which is close to, but outside the claim 8 range of 5.5 and 7.5. However, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. MPEP § 2144.05(I). Here the concentration of H+ does not distinguish over the cited art. See footnote 3.
Claim 9 recites:
9. The composition of claim 1, wherein the composition comprises more than 50 μM of the polypeptide.
In the chemical arts molarity or moles per liter is indicated by a capital M. Claim 9 therefore literally reads as ‘comprises more than 50 μmols polypeptide per liter of the composition’. See e.g., Hawley's Condensed Chemical Dictionary, page 944 (16th ed., 2016, R.J. Larrañaga ed.). Per the above experimental excerpt, Messina’s composition comprises 0.1 μmol of peptide in the 300 μL, which is 333 μM and therefore meets the molarity limitations of claim 9. Montgomery at page S30. One of ordinary skill is therefore motivated by Messina’s disclosed peptide molarity (M) to optimize the polypeptide in the above-proposed method to within the claimed concentration range of “more than 50 μM of the polypeptide”. MPEP § 2144.05(II); see also footnote 3.
The limitations of claim 10 are met because in practice of the cited art as proposed the gold complex reacts with the poly peptide to form the PEG-aryl-polypeptide conjugate, which corresponds to the claim 10 “cysteine-aryl conjugated polypeptide”. In other words, at some time point after mixing the gold complex and polypeptide, the PEG-aryl-polypeptide conjugate will also be present; at least until and if the mPEG-Au(III) and DARPin are completely reacted. Thus, all three required claim 10 components are present in in the proposed composition.
Claim Rejections 35 U.S.C. 112(a) – Written Description
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.
For an originally filed claim, 35 U.S.C. 112(a) requires that the specification shall contain a written description of the invention demonstrate that the inventor was in possession of the invention that is claimed.4 MPEP § 2163(I); MPEP § 2163(II)(A)(3)(a). Possession may be shown by disclosure of drawings or structural chemical formulas that show that the invention was complete. MPEP § 2163(I).
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 inventor was in possession of the claimed genus. MPEP § 2163(II)(A)(3)(a)(ii). A "representative number of species" means that the species which are adequately described are representative of the entire genus. MPEP § 2163(II)(A)(3)(a)(ii). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. MPEP § 2163(II)(A)(3)(a)(ii) (citing AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Implicit Function Recited in Claim 10
Claim 10 recites:
10. The composition of claim 1 further comprising a cysteine-aryl conjugated polypeptide.
Here, the claim 1 “composition” clearly requires at least two separate chemical entities as a mixture: (1) a polypeptide having at least one residue having a free thiol (e.g., cysteine); and (2) a gold(III) aryl complex comprising a polyethylene glycol group. Specification at page 5, lines 9-27; MPEP § 2111.
The specification teaches that the sole purpose of the claim 1 composition is that the components function to react with each other so as to form the claim 10 “a cysteine-aryl conjugated polypeptide”. Specification at paragraph bridging pages 8-9; see also, Fig. 3. In view of the specification, the language of claim 10 directs one of skill to employ only those gold(III) aryl complexes that function so as react with cysteine-containing polypeptides to form the claim 10 “a cysteine-aryl conjugated polypeptide”. MPEP § 2163(I).
The § 112(a) rejection
Claim 10 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement because neither the application as filed nor the art of record discloses:
(1) sufficient species of (per claim 1):
claim 1 . . . gold(III) aryl complex, the gold(III) aryl complex comprising a polyethylene glycol group having an average molecular weight greater than 1 kDa attached to the aryl group.
that function to react with “polypeptide having at least one cysteine residue” thereby forming the claim 10 “cysteine-aryl conjugated polypeptide; or
(2) a structure-function correlation between the full scope of the claimed gold (III) aryl complex comprising a polyethylene glycol group and the polypeptide having at least one cysteine residue,
such that one of skill can recognize which claimed gold (III) aryl complex comprising a polyethylene glycol group function (as required by claim 10) to react with polypeptide having at least one cysteine residue thereby forming the claim 10 cysteine-aryl conjugated polypeptide.
Guidance and Predictability
It is first noted that what is conventional or well known to one of ordinary skill in the art need not be disclosed in detail. MPEP § (II)(A)(3)(a). Thus, the state of and predictability in the art is a relevant consideration in determining compliance with § 112(a), written description. MPEP § (II)(A)(3)(a) (citing Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1085 (Fed. Cir. 2005) ("The ‘written description’ requirement must be applied in the context of the particular invention and the state of the knowledge…. As each field evolves, the balance also evolves between what is known and what is added by each inventive contribution”).
The specification teaches that protein and peptide therapeutics represent a large class of treatments for a plethora of diseases. Specification at page 1, lines 18-19. The specification teaches that conjugation of synthetic polymers significantly increases both the stability and in vivo lifetime, making the application of proteins and peptides as disease treatments more feasible and effective; where polyethylene glycol (PEG) comprises the polymer component of all of the 27 protein-polymer conjugates that are approved by the FDA. Specification at page 1, lines 20-26.
The specification teaches only one species of “gold(III) aryl complex . . . comprising a polyethylene glycol group” (i.e., (Me-DalPhos)AuCl) conjugated with either 2 kDa mPEG, 5 kDa mPEG, or 10 kDa mPEG. This species is depicted below.
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See specification at page 18, line 28 – page 19, line 18; Id. at Fig. 2.
The art of record does not supplement the scarcity of disclosed gold (III) species. Other than Messina’s gold (III) aryl complex comprising a polyethylene glycol group of 0.5 kDa (i.e., complex 2o, as discussed above in the § 103 rejection), searches identified no additional art teaching pegylated gold(III) aryl complexes that perform the claim 10 function of conjugating polyethylene glycol to polypeptides. And as discussed above Messina’s gold (III) aryl complex 2o differs from the instantly disclosed species only in that the polyethylene glycol (PEG) group has a molecular weight of 0.550 kDa, whereas the disclosed species comprise PEG of greater molecular weight.
Here, the disclosed species is structurally complex, having both nitrogen and phosphorous bonds. Extension of the disclosed species to other gold (III) complexes that react with the cysteine residue under reaction conditions that do not denature the peptide is necessarily challenging, particularly in view of inherent instability of peptides. Veronese at page 315, col. 1.
Outside of the single disclosed species, there is no general paradigm/model allowing one of skill to structurally predict gold(III) aryl complexes comprising a polyethylene glycol group that function to react with polypeptide having at least one cysteine residue thereby forming the claim 10 cysteine-aryl conjugated polypeptide..
In summary of above, the art is unpredictable and the specification teaches only one species of gold (III) aryl complex comprising a polyethylene glycol group that performs the claimed function.
Claim Breadth
Claim breath is relevant to the instant § 112(a) written description rejection. The written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. MPEP § 2163(II)(A)(3)(a)(ii) (citing Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021)).
The genus of “gold(III) aryl complex, the gold(III) aryl complex comprising a polyethylene glycol group having an average molecular weight greater than 1 kDa attached to the aryl group” is conceptually broad.
The specification does not specifically define the Markush genus of “a gold(III) aryl complex. . . comprising a polyethylene glycol group” by way of chemical structure. The specification teaches the following:
The gold(III) aryl complex comprises a gold(III) ion with a ligand set that stabilizes the gold(III) complex. The ligand set can be a 2-(di(alkyl)phosphino)-N,N-dimethylaniline, such as shown in exemplary Scheme 1 where R1 is a cycloalkyl or an alkyl. The cycloalkyl group may be monocyclic, bicyclic, tricylic, or polycyclic. Au complexes can be formed as shown in Scheme 1 with any combination of ligand sets and PEG-substituted aryl groups.
Specification a page 5, lines 22-27 (emphasis added). The term “gold(III) aryl complex . . . comprising a polyethylene glycol group” is thus broadly and reasonably interpreted, consistently with the specification, and according to its plain meaning, as a complex comprising: (1) gold (III); (2) undefined stabilizing ligand(s); (3) an aryl group; and (4) a polyethylene glycol group having an average molecular weight greater than 1 kDa attached to the aryl group. The specification does not teach or provide any guidance as to ligands (other than that of the disclosed species) that provides the required stabilizing function or that impart the capability of reacting with cysteine-containing polypeptides to form the claim 10 “a cysteine-aryl conjugated polypeptide”.
Claim 10 Lacks an Adequate Supporting Written Description
Claims 10 fails to comply with the written description requirement because neither the application as filed nor the art of record discloses: (1) sufficient species of (per claim 1):
claim 1 . . . gold(III) aryl complex, the gold(III) aryl complex comprising a polyethylene glycol group having an average molecular weight greater than 1 kDa attached to the aryl group.
that function to react with “polypeptide having at least one cysteine residue” thereby forming the claim 10 “cysteine-aryl conjugated polypeptide; or (2) a structure-function correlation between the full scope of the claimed gold(III) aryl complex comprising a polyethylene glycol group and the polypeptide having at least one cysteine residue, such that one of skill can recognize which claimed gold(III) aryl complex comprising a polyethylene glycol group function to react with polypeptide having at least one cysteine residue thereby forming the claim 10 cysteine-aryl conjugated polypeptide.
Here, Applicant is not in possession of the full claim scope because neither the specification nor the art of record provides sufficient guidance (representative species or a structure-function relationship) allowing one of skill to correctly predict those gold (III) aryl complexes comprising a polyethylene glycol group that perform the implicit claim 10 function of reacting with polypeptide having at least one cysteine residue thereby forming the claimed cysteine-aryl conjugated polypeptide.
The specification does not disclose a representative number of species. As discussed above, the specification discloses one species of “gold(III) aryl complex . . . comprising a polyethylene glycol group” (i.e., (Me-DalPhos)AuCl) conjugated with either 2 kDa mPEG, 5 kDa mPEG, or 10 kDa mPEG. Here, the structure recited within the claimed Markush genus of “gold(III) aryl complex . . . comprising a polyethylene glycol group . . . attached to the aryl group” is minimal because a structural definition of the ligands at the reactive gold core is absent.5 A "representative number of species" means that the species which are adequately described are representative of the entire genus. MPEP § 2163(II)(A)(3)(a)(ii); see also, Idenix Pharms. LLC v. Gilead Scis. Inc., 941 F.3d 1149, 1164 (Fed. Cir. 2019) (“[a]s a result, a POSA is deprived of any meaningful guidance into what compounds beyond the examples and formulas, if any, would provide the same result”). Here the single disclosed species is not representative of the conceptually vast claimed genus.
Further, neither the art nor the specification shows a well-established correlation between the structure of the claimed “gold(III) aryl complex . . . comprising a polyethylene glycol group” and the function of polypeptide conjugation. As discussed above, the instantly disclosed species (as disclosed in prior art Messina, but with a lower molecular weight PEG group) appears to be the only species capable of performing the claimed function.
Conclusion
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 Messina’s tripeptide glutathione meets the meaning of claim 1 “polypeptide”. The specification defines “polypeptide” as follows:
Disclosed herein is a composition comprising a polypeptide having at least one residue having a free thiol (e.g., cysteine) and a gold(III) aryl complex. The polypeptide can be a protein or fragment thereof, for example an enzyme, hormone, structural protein, storage protein, contractile protein, an antibody, or an immunoglobulin. The polypeptide can comprise a multiplicity of amino acids residues. Polypeptides may have 10, 50, 100, 150, 200, or 250 or more amino acid residues.
Specification at page 5, lines 9-14 (emphasis added).
2 One of ordinary skill is motivated to develop workable or optimum ranges for result-effective parameters, where Applicant can rebut a prima facie case of obviousness by showing the criticality (unexpected result) of the range. MPEP § 2144.05; see also, In re Boesch, 617 F.2d 272,276 (CCPA 1980); In re Aller, 220 F.2d 454, 456 (CCPA 1955).
3 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 § 2144.05(II)(A) (citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
4 While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, a question as to whether a specification provides an adequate written description may arise in the context of an original claim. MPEP § 2163.03 (V) (citing In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976)). An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. MPEP § 2163.03 (V) (citing Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) ("[e]ven if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed”).
5 The written description requirement may also be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. MPEP § 2163(II)(A)(3)(a)(i). In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. MPEP § 2163(II)(A)(3)(a)(i) (citing Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406).