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 .
Priority
This Application is CON of PCT/US2022/014325, filed 01/28/2022 and claims domestic priority benefit of U.S. Provisional Application Nos. 63/186,005 and 63/144,442 filed Feb. 1, 2021 and May 7, 2021, respectively.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on Jan. 28, 2024 and July 31, 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Status
Claims 1-22 are currently pending and subject to examination.
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 1-3, 11-17 and 21-22 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.
Claim 1 is directed towards: “A targeting group conjugated PROTAC, wherein ubiquitin recruitment for the PROTAC only occurs following hydrolytic or reductive cleavage of the targeting group.”
Claim 1 recites the limitation "the PROTAC" in line 1. There is insufficient antecedent basis for this limitation in the claim because “the PROTAC” is not the same as the “targeting group conjugated PROTAC” previously introduced. Claim 1 recites the limitation "the targeting group" in line 2. There is insufficient antecedent basis for this limitation in the claim because “the targeting group” similarly lacks explicit antecedent basis because it was only introduced as a part of the compound phrase.
Furthermore, one of ordinary skill in the art cannot determine the metes and bounds of the claim because of structural indefiniteness. The claim recites that “ubiquitin recruitment… only occurs following cleavage” – This describes a functional result that depends on biological conditions, not a structural feature of the compound itself. I.e. “Only occurs following cleavage”: describes a sequence of biological events, not a structural feature. The claim defines the invention by what is does (functional result) rather than what it is (structure). The MPEP states:
Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous:
(1) whether there is a clear cut indication of the scope of the subject matter covered by the claim;
(2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and
(3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim.
MPEP 2173.05(g).
The scope of the subject matter covered by the claim is unclear because what level of pre-cleavage recruitment is not within the scope of the claimed invention? There is no clear boundary because the term “only” is an absolute term that is difficult to verify. Does 1% pre-cleavage recruitment violate “only”? 5%? 10%?
One of ordinary skill in the art would also not know from the claim what structure or steps are encompassed by the claim because it is unclear if the PROTAC is structurally designed so that it can only recruit ubiquitin after cleavage or if the PROTAC does not recruit ubiquitin until cleavage occurs in practice. The phrase “ubiquitin recruitment… only occurs following cleavage” describes a biological phenomenon which may depend on external factors:
pH (affects hydrolysis rate)
presence of reducing agents (for reductive cleavage)
enzyme levels (ubiquitin ligase concentration)
temperature
cell type
The same compound might show “only following cleavage” recruitment in one assay, some pre-cleavage recruitment in another assay, or show different behavior in different cell types. The claim purports to claim a chemical structure (a compound) but defines it in functional terms that do not provide certainty about what structures fall within the scope because the results vary by condition, no thresholds are specified and the relationship between structure and function is unclear.
Claim 2 recites the limitation "said PROTAC" in line 1. There is insufficient antecedent basis for this limitation in the claim because “the PROTAC” was not the same as the “targeting group conjugated PROTAC” previously introduced in claim 1 so it is unclear if “said PROTAC” refers to the targeting group conjugated PROTAC or the new PROTAC at the end of line 1 of claim 1. The phrase “wherein said PROTAC is conjugated to folate, fluorodeoxyglucose or biotin moiety” is also structurally unclear because this could mean:
The folate/ FDG/ biotin is the targeting group mentioned in claim 1;
The folate/FDG/biotin is conjugated to the targeting group conjugated PROTAC as an additional moiety (beyond the targeting group).
The folate/FDG/biotin is conjugated to a PROTAC without a targeting group.
Therefore, the current claim language leaves a skilled artisan uncertain about the actual structure being claimed.
Claim 3 is directed towards:
A compound having the structure of formula (I): PB-L1-ULB-L2-TG,
wherein ULB is a ubiquitin ligase binding moiety,
L1 is absent or a linker,
L2 is absent or a linker,
PB is a protein binding moiety; and
TG is a targeting group that preferentially binds to a protein with increased expression in a neoplastic cell compared to an otherwise identical healthy cell;
wherein the ubiquitin ligase binding potential of said compound is increased following cleavage between the ULB group and the TG group.
The metes and bounds of this claim are unclear because it contains a “wherein clause” (“wherein the ubiquitin ligase binding potential of said compound is increased following cleavage between the ULB group and the TG group”) which adds a functional requirement without clearly limiting the structure. The claim already defines the structure as A compound having the structure of formula (I): PB-L1-ULB-L2-TG, and it is unclear how the wherein clause further limits the claimed structure. It is also unclear what the term “binding potential” means as it is not defined in the specification and is not a usual term of art. Does this mean i) actual measured binding; ii) theoretical capability to bind; iii) binding affinity (Kd)?; iv) binding rate (Kon)? Furthermore, the scope of the claim is unclear because “increased” binding potential is a term of degree with no baseline or threshold specified. Is any increase sufficient to meet the claim? 1.1-fold? 2-fold? 10-fold? 100-fold? As stated in the MPEP, an ordinary artisan must be able to ascertain the requisite degree required for functional language:
When a claim limitation employs functional language, the examiner’s determination of whether the limitation is sufficiently definite will be highly dependent on context (e.g., the disclosure in the specification and the knowledge of a person of ordinary skill in the art). Halliburton Energy Servs., 514 F.3d at 1255, 85 USPQ2d at 1663. For example, a claim that included the term “fragile gel” was found to be indefinite because the definition of the term in the specification was functional, i.e., the fluid is defined by what it does rather than what it is (“ability of the fluid to transition quickly from gel to liquid, and the ability of the fluid to suspend drill cuttings at rest”), and it was ambiguous as to the requisite degree of the fragileness of the gel, the ability of the gel to suspend drill cuttings (i.e., gel strength), and/or some combination of the two. Halliburton Energy Servs., 514 F.3d at 1255-56, 85 USPQ2d at 1663.
MPEP § 2173.05(g).
Regarding the definition of TG: “TG is a targeting group that preferentially binds to a protein with increased expression in a neoplastic cell compared to an otherwise identical healthy cell”, this phrase is indefinite because:
“Preferentially binds” is not a term of art with a fixed quantitative meaning and this term is not defined in the specification. It could mean higher affinity (Kd), faster association rate, greater occupancy at physiological concentrations, or simply greater binding due to greater protein abundance. Without a well-defined metric or threshold, a person of ordinary skill in the art cannot determine with reasonable certainty whether a compound satisfies this metric.
“Protein with increased expression in a neoplastic cell” is indefinite because the identity of the protein is undefined and could read as if any protein with higher expression in a cancer cell could satisfy it. This includes so many alternatives and is so expansive, that a person of ordinary skill in the art cannot determine the metes and bounds of the proteins and potential ligands. One of ordinary skill in the art could not envision all of the members of the group (see MPEP § 2173.05(h)).
“Otherwise identical healthy cell” is inherently indefinite because this is conceptually impossible – no two cells are “identical” except for neoplastic transformation.
Claim 11 is dependent on claim 1 and recites: “The compound of claim 1, wherein said compound has the structure of formula (III):
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One of ordinary skill in the art cannot determine the metes and bounds of the claim because neither claim 1 or claim 11 define L1, PB, L2 or TG. The Specification provides many possibilities for L1, PB, L2 and TG, and without a definition for these groups in the claim, a person of ordinary skill in the art cannot determine with reasonable certainty what chemical structures fall within the scope of claim 11. Claim 12 is dependent on claim 11 and also does not define these groups and is therefore also indefinite.
Claim 13 recites the limitation "L2" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 14, the phrase "e.g." (for example) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 14 recites the limitation "the ULB" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 14 recites:
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One of ordinary skill in the art cannot determine the metes and bounds of the claim because neither claim 1 or claim 14 define L1, PB, L2 or TG. The Specification provides many possibilities for L1, PB, L2 and TG, and without definitions for these variable groups in the claim, a person of ordinary skill in the art cannot determine with reasonable certainty what chemical structures fall within the scope of claim 14.
Claim 15 recites:
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One of ordinary skill in the art cannot determine the metes and bounds of the claim because neither claim 1 or claim 15 define L1, PB, L2 or TG. Without definitions for these variable groups, a person of ordinary skill in the art cannot determine with reasonable certainty what chemical structures fall within the scope of claim 15. Claim 16 is dependent on claim 15 and also does not define these groups and is therefore also indefinite.
Claim 17 recites: “The compound of claim 1, wherein said compound has the structure of one of…
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This claim is indefinite for multiple reasons. First, one of ordinary skill in the art cannot determine the metes and bounds of the claim because neither claim 1 or claim 17 define L1, PB, L2 or TG. Without definitions for these variable groups, a person of ordinary skill in the art cannot determine with reasonable certainty what chemical structures fall within the scope of claim 17.
Second, it is unclear if X3 is only
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or if X3 is the entirety of
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(Vc). There is also not a clear conjunction between the formula (Vc) and (Vd) so it is unclear if this is an alternative for X3 or the entire structure of the compound of claim 1.
Next, there is a period following -S-S- before formula (VI), (VIa) or (VIb). Claims must be in one sentence only. It is unclear how and if the subject matter following the period is incorporated into the claim.
Claim 21 recites, the compound of claim 3, wherein said compound has the structure of formula (VIIa), (VIIb), (VIIc), (VIId), (VIIf), (VIIg), (VIIh), (VIIi), (VIIj), (VIIk), (VIl), (VIIm), or (VIIn). The metes and bounds of claim 21 are unclear because claim 21 shows the structures of the aforementioned compounds but then also introduces compounds 1, 2, 3, and 4. It is unclear if compounds 1-4 are claimed subject matter because they are not mentioned in the text of the claims and they are not designated as compounds of the aforementioned formulae.
Claim 22 recites the limitation "the ubiquitin ligase binding group" in line 3. There is insufficient antecedent basis for this limitation in the claim. This term appears for the first time in this method claim. Claim 1 does not mention any “ubiquitin ligase binding group.”
The term “increase binding affinity” in claim 22 is a relative term which renders the claim indefinite. The term “increase binding affinity” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what is the increase? Is it an increase compared to what baseline? By how much? (any increase? 2-fold? 10-fold?) This is an unmeasured results-based limitation.
The claim in general mixes method steps (e.g. contacting) with results (“cleave,” “increase binding affinity”) without clarity about:
Whether the results must actually occur for infringement;
How to measure whether the results occurred; and
What degree of result is required.
An ordinary artisan would not know if the claim requires them to achieve the results or just perform the steps. For example, if they contact a protein with the compound and perform hydrolysis and cleaving only occurs 50% of the time, or binding affinity only increases by 5%, is this within the scope of the claim? Another artisan performs the exact same steps, but uses conditions where cleavage is 95% efficient, is this the same claim scope?
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
“(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
“Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
Claim 20 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 20 is dependent on claim 21, and defines Y3. Claim 20 is not dependent upon a claim previously set forth because claim 21 was not previously set forth. Claim 21 also does not include Y4 so a definition for Y4 is not further limiting to claim 21.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
“Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.”
Claim 22 rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon/ law of nature without significantly more. The claim(s) recite(s) “A method for degrading a protein of interest” which is a natural biological process. This judicial exception is not integrated into a practical application because no specific medical treatment steps are required. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because contacting a protein with a compound is a routine laboratory technique and activating through hydrolysis is a natural process, not an inventive step.
Step 1: Is the claim to a process, machine, manufacture or composition of matter? YES. The claim is directed towards a process.
Step 2A, Prong 1: Is the claim directed to a law of nature, natural phenomenon, or abstract idea? YES.
The claim is directed to multiple natural phenomenon:
Natural chemical reaction (hydrolysis)
Natural biological process (ubiquitin mediated proteolysis)
Natural molecular recognition (increased binding affinity after unmasking)
Step 2A, Prong 2: Does the claim recite additional elements that integrate the judicial exception into a practical application? NO.
The claim does not include additional elements such as applying or using the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. The claim merely recites steps such as “contacting the protein of interest with a compound of claim 1” which is routine and conventional, a standard laboratory technique of mixing reagents. “Activating the compound through hydrolysis” is just a natural process, and just relies on natural water mediated bond cleavage. “To cleave the targeting group from the ubiquitin ligase” is just the result of the natural hydrolytic process. “Increase the binding affinity of the compound to the ubiquitin ligase” is just another natural result.
Step 2B: Does the claim amount to significantly more than the judicial exception and provide an inventive concept? NO.
The claim as a whole requires:
Take a compound
Add it to a protein
Let hydrolysis occur
Observe natural results (cleavage, binding increase).
This is insufficient to amount to more than the judicial exception because there are no steps beyond contacting and letting the reaction occur. The claim doses not teach anything inventive and just requires the artisan to observe what happens naturally. Just using the compound in a routine laboratory assay is a basic tool of scientific and technological work, and does not amount to more than the exception.
Claim Rejections - 35 USC § 102
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.”
Claim(s) 1, 3, 7-13 and 18-22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maneiro et al. (ACS Chemical Biology, Vol. 15, Issue 6, Published April 27, 2020, p. 1306-1312).
Claim 1 is directed towards: “A targeting group conjugated PROTAC, wherein ubiquitin recruitment for the PROTAC only occurs following hydrolytic or reductive cleavage of the targeting group.”
Mainero teaches a targeting group conjugated PROTAC, wherein ubiquitin recruitment for the PROTAC only occurs following hydrolytic or reductive cleavage of the targeting group. Mainero teaches that the targeting group conjugated PROTAC is a trastuzumab-PROTAC conjugate (Ab-PROTAC 3) which “could achieve selective delivery of a PROTAC and direct protein degradation specifically in HER2+ cells.” (Mainero, col. 1, p. 1307). The Ab-PROTAC3 is “caged with an antibody linker which can be hydrolyzed following antibody− PROTAC internalization, releasing the active PROTAC and inducing catalytic protein degradation.” (Mainero, Abstract). The Ab-PROTAC3 “was synthesized by rebridging the interchain disulfide bonds of trastuzumab with next-generation maleimides (NGMs), giving access to constructs with controlled PROTAC loading and robust serum stability, ensuring PROTAC release solely via hydrolysis of the cleavable ester linker” (Mainero, col. 1, p. 1309). The active PROTAC triggers “directed polyubiquitination and subsequent proteasome-mediated degradation of the POI, in a manner that is catalytic, with respect to the PROTAC.” (Mainero, col. 1, p. 1306).
Therefore, claim 1 is anticipated.
Claim 3 is directed towards:
A compound having the structure of formula (I): PB-L1-ULB-L2-TG,
wherein ULB is a ubiquitin ligase binding moiety,
L1 is absent or a linker,
L2 is absent or a linker,
PB is a protein binding moiety; and
TG is a targeting group that preferentially binds to a protein with increased expression in a neoplastic cell compared to an otherwise identical healthy cell;
wherein the ubiquitin ligase binding potential of said compound is increased following cleavage between the ULB group and the TG group.
Mainero teaches a compound having the structure of formula (I): PB-L1-ULB-L2-TG, wherein ULB is a ubiquitin ligase binding moiety, L1 is a linker, L2 is a linker, PB is a protein binding moiety; and TG is a targeting group that preferentially binds to a protein with increased expression in a neoplastic cell compared to an otherwise identical healthy cell; wherein the ubiquitin ligase binding potential of said compound is increased following cleavage between the ULB group and the TG group:
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Mainero, Fig. 1B-E, p. 1307.
Our conjugation strategy required attachment of the PROTAC to trastuzumab through a triazole moiety. We decided to take advantage of the free hydroxyl group on the VHL ligand moiety of 1 to tether an azido-PEG linker. This hydroxyl group in 1 is essential for binding to VHL; (36,37) hence, attaching an antibody linker to this position via an ester (see Figure1B, as well as Scheme S1 in the Supporting Information) would effectively cage PROTAC activity until it is released intracellularly during lysosomal digestion of the conjugate. Thus, our tool compounds PROTAC 1 and azido-PROTAC 2 were synthesized as reported in Scheme S1.
Antibody–PROTAC conjugate 3 was synthesized by rebridging the interchain disulfide bonds of trastuzumab with next-generation maleimides (NGMs), giving access to constructs with controlled PROTAC loading and robust serum stability, ensuring PROTAC release solely via hydrolysis of the cleavable ester linker. (38−41)
Mainero, col. 1, p. 1309 (emphasis added);
We examined the biological activity of 3 against two HER2 negative (HER2−) breast cancer cell lines (MCF-7 and MDA-MB-231) and two HER2+ breast cancer cell lines (SK-BR-3 and BT-474), selected based on HER2/neu receptor and BRD4 expression levels determined by Western blot and immunofluorescence (see Figures 2A and 2B) and the confirmed capacity of free PROTAC 1 to degrade BRD4 in each of these cell lines under the same conditions selected for testing Ab-PROTAC 3 (Figure2C)… BRD4 abundance was analyzed by SDS-PAGE, followed by Western blot analysis (Figure2D), showing that Ab-PROTAC 3 selectively degrades BRD4 only in HER2+ cells while leaving BRD4 intact in HER2– cells. 100 nM Ab-PROTAC 3 for 4 h delivered almost-complete BRD4 depletion only in HER2+ cell lines.
Mainero, p. 1309-1310.
Therefore, claim 3 is anticipated.
Claim 7 is directed towards the compound of claim 3, wherein the -L2-TG is conjugated to the ULB through a hydroxyl group required for ubiquitin ligase binding. As shown in the rejection of claim 3, Mainero conjugates the - L2-TG to the hydroxyl group required for ubiquitin ligase binding.
Therefore, claim 7 is anticipated.
Claim 8 is directed towards the compound of claim 7, therein the conjugation through a hydroxyl group is an ester conjugation. As shown in the rejection of claim 3, the conjugation through a hydroxyl group is an ester conjugation.
Therefore, claim 8 is anticipated.
Claim 9 is directed towards the compound of claim 3, wherein said ULB binds to an E3 ubiquitin ligase following cleavage. As shown in the rejection of claims 1 and 3, the ULB is caged until cleavage occurs.
Therefore, claim 9 is anticipated.
Claim 10 is directed towards the compound of claim 9, wherein the E3 ubiquitin ligase is selected from the group consisting of von Hippel Lindau (VHL) E3 ubiquitin ligase, (3-Transducin Repeat Containing (p-TRCP) E3 Ubiquitin Protein Ligase, Mouse Double Minute 2 (Mdm2) E3 Ubiquitin Protein Ligase, and a Cereblon (CRBN) E3 Ubiquitin ligase.
Mainero teaches that the “PROTACs of this class feature BET bromodomain ligand JQ1 as a targeting element for BET-containing proteins (such as BRD4) linked to a ligand for von Hippel−Lindau protein (VHL), which is a key component of an E3 ligase complex involved in the regulation of hypoxia.” (Mainero, col. 2, p. 1307 (emphasis added)).
Therefore, claim 10 is anticipated.
Claim 11 is directed towards the compound of claim 1, wherein said compound has the structure of formula (III):
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. As shown in the rejection of claim 3, the compound of Mainero has the structure of formula (III). Therefore, claim 11 is anticipated.
Claim 12 is directed towards the compound of claim 11, wherein the compound has a structure of formula:
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. As shown in the rejection of claim 3, the compound of Mainero has the structure of formula (IIIe). Therefore, claim 12 is anticipated.
Claim 13 is directed towards the compound of claim 1, wherein L2 comprises a heteroarylene group, -C(O)-, -NH-, or combinations thereof.
For the purpose of comparing with the prior art, claim is interpreted to read on the compound of claim 3, because claim 1 does not mention L2. As shown in the rejection of claim 3, the compound of Mainero comprises combinations of heteroarylene group, -C(O)-, and -NH-. Therefore, claim 13 is anticipated.
Claim 18 is directed towards the compound of claim 3, wherein PB is
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. As shown in the rejection of claim 3, in the compound of Mainero, PB is
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. Therefore, claim 18 is anticipated.
Claim 19 recites:
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[AltContent: rect]In the compound of Mainero L1 is indicated in the following box:
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. As such, claim 19 is anticipated.
Claim 20 is interpreted as to depend from claim 19 for the purposes of applying the prior art. Claim 20 is directed towards the compound, wherein Y4 is
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, as in Mainero above. Therefore, claim 20 is anticipated.
Claim 21 is directed towards the compound of claim 3, wherein the compound has the structure of formula (VIIm):
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. As shown above, the compound of Mainero has the structure of (VIIm).
Therefore, claim 21 is anticipated.
Claim 22 is directed towards: “A method of degrading a protein of interest, the method comprising contacting the protein of interest with a compound of claim 1 and activating the compound through hydrolysis to cleave the targeting group from the ubiquitin ligase binding group and increase the binding affinity of the compound for the ubiquitin ligase.”
Mainero teaches a method of degrading a protein of interest, the method comprising contacting a protein of interest with a compound of claim 1, activating the compound through hydrolysis to cleave the targeting group from the ubiquitin ligase binding group and increase the binding affinity of the compound for the ubiquitin ligase:
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Mainero, Fig. 1a, Proposed mode of action of an antibody−PROTAC conjugate, resulting in HER2-dependent protein degradation, p. 1307.
Fig. 1a. illustrates the concept described in the rejection of claim 1 above. The Ab-PROTAC3 is applied to the cell (contacting the protein of interest), internalized into the cell, hydrolyzed to release the active PROTAC, which mediates ubiquitin dependent targeted protein degradation.
Therefore, claim 22 is anticipated.
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 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.
Claim(s) 1-13, 15-16 and 18-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maneiro et al. (ACS Chemical Biology, Vol. 15, Issue 6, Published April 27, 2020, p. 1306-1312), as applied to claims 1, 3, 7-13 and 18-22 above, and further in view of Cao et al. (US 2021/0369853 A1, PCT filed Oct. 9, 2019, effective filing date Oct. 9, 2018).
The rejection of claims 1, 3, 7-13, and 18-22 above as anticipated by Maneiro is incorporated herein by reference. Given the teachings of Maneiro, claims 1, 3, 7-13, and 18-22 were prima facie obvious at the time of filing.
Claim 2 is directed towards the targeting group conjugated PROTAC of claim 1, wherein said PROTAC is conjugated to folate, fluorodeoxyglucose or biotin moiety.
For the purposes of comparison to the prior art, this claim is interpreted to mean that the folate, fluorodeoxyglucose or biotin moiety is the targeting group and conjugated to a PROTAC to form a targeting group conjugated PROTAC.
As shown above, Maneiro teaches a targeting group conjugated PROTAC, wherein the targeting group is an antibody. While Maneiro does not teach a targeting group conjugated PROTAC wherein the targeting group is folate, fluorodeoxyglucose or biotin, one of ordinary skill in the art would have a reasonable expectation of success to replace the antibody with folate, fluorodeoxyglucose or biotin because it is commonly known in the art that these moieties can function as targeting groups which have improved properties as compared to antibody drug conjugates such as Maneiro’s.
For example, Cao teaches that folate, instead of an antibody, can be conjugated to E3 ligase ligands to provide targeted protein degradation in a specific cell population:
Disclosed is a targeted protease degradation platform (TED), which in particular is a conjugate of target molecule-linker-E3 ligase ligand as shown in the structure of A-L1-B (formula I), wherein the A is the monovalent group of the target molecule, the B is the monovalent group of the E3 ligase ligand, the L1 is the linker linking A and B, and L1 is as shown in —X-L2-Y— (formula II).
Cao, Abstract;
Antibody-drug conjugates (ADC) utilize endocytic antibodies to provide targeting and serve as carriers to deliver super toxin drugs to the targeted site. The bottleneck encountered in the development of ADC drugs is that the treatment window is not wide enough. In addition to the side effects caused by the antibody itself, the super toxins will fall off before reaching the targeting site due to the heterogeneity of coupling, and causing serious side effects. In addition, normal physiological function of ubiquitin-proteasome system is responsible for cleaning up denatured, mutated or harmful proteins in cells.
Cao, Specification, paragraph [0003];
In another preferred embodiment, the target molecule T and the target molecule A are each independently selected from the group consisting of folic acid, HSP90 inhibitor, and a combination thereof.
Cao, Specification, paragraph [0042].
Cao teaches specific examples of PROTACs conjugated to folic acid (folate):
[AltContent: rect]
[AltContent: textbox (Cleavable linker)][AltContent: textbox (PROTAC)][AltContent: rect][AltContent: textbox (Folate)]
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Cao, Specification, p. 322, paragraph [0992] (labels added by Examiner).
The above compound UB-180829, contains a PROTAC comprised of a ubiquitin binding moiety that is lenalidomide, a cereblon binding protein, and a protein binding moiety that is BI-2536, a PLK1 inhibitor, which is linked to a targeting moiety, folate, through a cleavable linker with a disulfide bond.
Therefore, claim 2 was prima facie obvious at the time of filing.
Claim 4 is directed towards the compound of claim 3, wherein the TG is a folate derivative or an FDG derivative or a biotin derivative. Claim 5 is directed towards the compound of claim 4, wherein the TG group is a folate derivative having the structure of formula (II):
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. Claim 6 is directed towards the compound of claim 1, wherein the TG group is a folate derivative having the structure of formula (IIa) or (IIb):
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.
While Maneiro does not teach that the TG is a folate derivative having a structure of formula (II), (IIa) or (IIb), one of ordinary skill in the art would have a reasonable expectation of success to substitute the antibody TG of Mainero with a folate derivative of formula (II), (IIa) or (IIb) because it is commonly known in the art that folate derivatives of these formulae can function as targeting groups for PROTACs.
For example, Mainero teaches a folate derivative of formula (II)/(IIb) conjugated to a PROTAC:
Cao teaches specific examples of PROTACs conjugated to folic acid (folate):
[AltContent: textbox ((IIb))][AltContent: rect]
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Cao, Specification, p. 322, paragraph [0992] (labels added by Examiner).
Therefore, claims 4-6 were prima facie obvious at the time of filing.
Claim 15 is directed towards the compound of claim 1, wherein said compound has the structure of formula (V):
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wherein X1-X7 are independently selected from absent, -C(O)-, -O-, OC(O)-, NRa-, N(Ra)C(O)-, -(C(Ra)(Ra))1-8-, -(C(Ra)(Ra)C(Ra)(Ra)O)1-8-, -S-S-, arylene, and heteroarylene, and R8 is independently selected at each occurrence from hydrogen and alkyl.
Mainero teaches the following linker (X1-X7):
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(Mainero, Fig. 1). This is so similar to the linker of claim 15 that one of ordinary skill in the art would expect similar properties. The only difference is that -(C(Ra)(Ra)C(Ra)(Ra)O)1-8 is -(OC(Ra)(Ra)C(Ra)(Ra))1-8. It is commonly known in the art that linkers can contain C, O, and N atoms in different orders and the order of the atoms in the linker has little impact on the function. For example, Mainero teaches that the linker may be:
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Mainero, Specification, p. 6.
Therefore, claim 15 was prima facie obvious at the time of filing.
Claim 16 is directed towards the compound of claim 15, wherein one of X3-X5 is
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Mainero teaches a similar moiety:
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. While Mainero does not teach the exact moiety as instantly claimed, one of ordinary skill in the art would have a reasonable expectation of success to make a targeted PROTAC wherein at least one of X3-X5 is
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because similar linkers are commonly known in the art. For example, Mainero teaches that the linker may comprise:
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(Mainero, Specificatoin, p. 9, paragraph [0112]).
Therefore, claim 16 was prima facie obvious at the time of filing.
Claim(s) 1-16 and 18-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maneiro et al. (ACS Chemical Biology, Vol. 15, Issue 6, Published April 27, 2020, p. 1306-1312), as applied to claims 1, 3, 7-13, 18-19 and 22 and Cao et al. (US 2021/0369853 A1), as applied to claims 1-13, 15-16, and 18-22 above, and further in view of Stewart et al. (Organic & Molecular Biochemistry, 2010, 8, 4059–4062)
The rejection of claims 1-13, 15-16 and 18-22 above as obvious over Maneiro in view of Cao is incorporated herein by reference.
Claim 14 is directed towards the compound of claim 1, wherein the compound has the structure of formula (IV):
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.
As shown above, Mainero teaches a TG conjugated PROTAC of formula PB-L1-ULB-L2-TG and that the ULB in the PROTAC of claim 1 is
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(Mainero, Fig. 1). While Mainero does not teach that the ULB-L2-TG is
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, one of ordinary skill in the art would have a reasonable expectation of success to substitute the ULB-L2-TG for
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because similar ULB-TGs are commonly known in the art.
For example, Cao teaches that the ULB may be
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(Cao, Specification, p. 32, paragraph [0124]) and Stewart explicitly teaches that a TG (biotin) can be conjugated to an E3 ligase ligand as in claim 14:
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(Stewart, p. 4060).
Therefore, claim 14 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
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/HEATHER DAHLIN/Examiner, Art Unit 1629