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 . 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.
Examiner’s Note
Prosecution of this application has passed to Fred Reynolds from Brendan Oliss.
Election/Restrictions
Applicants elected chimeric compounds and methods using them, specifically, the last compound of fig 7 without traverse in the response of 6 Feb, 2026.
Claims Status
Claims 1-5, 11, 17, 48, 51, 53, 54, 65, 66, 79, 81-94 are pending.
Claims 1, 5, 65, and 81-83 have been amended.
Claims 85-94 are new.
Claims 11, 17, 65, 66, and 84-94 have been withdrawn due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claim 54 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is hereby withdrawn due to lack of an explanation of what the issue is.
The rejection of claim 65 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph due to claim limitations referred to in the figures is hereby withdrawn due to amendment.
The rejection of claims 82 and 83 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph due to missing limitations and illegible figures is hereby withdrawn due to amendment.
The rejection of claims 1, 4, 51, 53, and 54 under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al. (Liu, Yuzhi et al. “The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020.” European journal of medicinal chemistry vol. 206 (2020): 112711; made available online 6 August 2020) is hereby withdrawn due to amendment.
The rejection of claims 1-5, 22, 48, 51, 53, 54, 65, 66, and 79-81 under 35 U.S.C. 103 as being unpatentable over Liu et al. (Liu, Yuzhi et al. “The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020.” European journal of medicinal chemistry vol. 206 (2020): 112711; made available online 6 August 2020) in view of Ratia et al. (Ratia, Kiira et al. “A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication.” Proceedings of the National Academy of Sciences of the United States of America vol. 105,42 (2008): 16119-24) and US 20190300576 A1, hereinafter Pentelute et al. (filed 2018-11-30 and published 2019-10-03), and in further view of Hines et al. (Hines, John et al. “MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53.” Cancer research vol. 79,1 (2019): 251-262) and US 9250238 B2, hereinafter Low et al., as evidenced by Uldrijan et al. (Uldrijan, Stjepan et al. “An essential function of the extreme C-terminus of MDM2 can be provided by MDMX.” The EMBO journal vol. 26,1 (2007): 102-12) is hereby withdrawn due to a missing limitation.
New Rejections
Claim Rejections - 35 USC § 112(a)
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
first rejection, written description
Claims 1-5, 48, 51, 53, 54, and 79-82 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person of skill in the art would understand what structures are required to bind to the various proteins.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants have described a small number of small molecule binders, and a small number of peptides. There is discussion of mutants of the peptides, but no discussion of where these sequences can be modified.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Claim 1 requires a moiety that binds to a coronavirus protein and a second moiety which must be a stapled peptide (no sequence specified) that recruits a protein degrader. Dependent claims give more specificity as to what proteins these moieties bind to, but all the rejected claims require at least one moiety that binds to a protein with little structural requirements. These are functional limitations; the first moiety has a function of binding to a coronavirus protein, and the second moiety has a functional limitation of recruiting a protein degrader. However, applicants have given no structural requirements to meet these functional limitations. A person of skill in the art would not know what aromaticity/sequence/hydrophobicity requirements are necessary to meet these functional limitations. In essence, applicants have claimed their invention by function. That is not sufficient to meet the written description.
Reynolds et al (PLoS ONE (2011) 6(7) e22471) discusses phage clones that bind to pancreatic cancer (5th page, 2nd column, 2nd paragraph). A number of different phage clones can bind to the same protein, without obvious sequence identity between the clones, note table 1, 6th page, 1st column, bottom of page.
As of applicant’s priority date, it was not possible to predict if a given molecule bound to a receptor. Lowe (blog “In the pipeline” entry of 7 Sept, 2022) describes an experiment where that was attempted. 39K compounds, including known antibiotics, were screened against E. coli for growth inhibition, finding 218 active compounds (1st page, 3d paragraph). These were computer docked to a set of 296 essential bacterial proteins by multiple docking procedures (1st page, 3d paragraph), along with 100 random inactive compounds (2nd page, 1st paragraph). The number of strong binders predicted were essentially the same between the active compounds and the controls, and out of 142 compound/target interactions previously known, the methodology found only 3 (2nd page, 2nd paragraph). While a given docking program may accurately predict if compound A binds to protein B, it is impossible to a priori know if the prediction is accurate. In other words, several years after applicant’s priority date, it was not possible to predict if a given compound and target bound to each other.
Nor is it possible to modify known sequences to reliably find new compounds. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about the binding, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
(d) representative number of samples: Applicants have listed a relatively small number of small molecule and peptide sequences that they say bind to the various components of the claims. However, many of these compounds are dubious for what applicants claim. For example, applicants list ritonavir as a protease binder for coronaviruses (table 1, p24). However, this drug is a protease inhibitor for HIV, not coronaviruses (Pereira et al (Curr. Oncol. (2024) 31 p6032-6049, p6033, 1st paragraph). While it is used in a coronavirus medication (Paxlovid), it is to compete with liver enzymes to prolong the lifetime of the drug that treats the coronavirus infection (p6035, 2nd paragraph). Given the small number of compounds that applicants disclose (and the questionability of some of the compounds for the purpose named by applicants), and the fact that even small conservative modifications are likely to abrogate activity, the claims lack written description.
second rejection, scope of enablement
Claims 51, 53, and 54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating coronaviruses that have proteins that bind to the first moiety, does not reasonably provide enablement for all RNA viruses. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The MPEP states “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is ‘undue.’ These factors include, but are not limited to: 1) the breadth of the claims; 2) the nature of the invention; 3) the state of the prior art; 4) the level of one of ordinary skill; 5) the level of predictability in the art; 6) the amount of direction provided by the inventor; 7) the existence of working examples; and 8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure” (MPEP 2164.01(a).
1 and 2) the breadth of the claims and the nature of the invention: Applicants are claiming a method of treating either SARS CoV/SARS CoV2, all coronaviruses, or all RNA viruses, comprising administering a compound that binds to a coronavirus protein.
3) the state of the prior art: Springfeld et al (Cancer Res. (2006) 66(15) p7694-7700) teaches that measles is an RNA virus (p7694, 2nd column, 2nd paragraph) that uses a host protease (abstract), rather than its own protease.
Dinata et al (Viruses (2025) 17 (722)) teaches that COVID-19 rapidly generates new variants, which diminish the neutralizing effects of vaccines (abstract) and antiviral drugs (2nd page, 2nd paragraph).
Guo et al (PNAS (2004) 101(25) p9205-9210) teaches that activity can often be abrogated by a single mutation, indicating that the compounds of claim 1 would be unlikely to bind to a mutated version of the protein (such as from a different virus).
4) the level of one of ordinary skill: The level of skill in the art is high.
5) the level of predictability in the art: The invention is in the field of biotechnology, which has a relatively high level of unpredictability (MPEP 2145(X)(E)).
6 and 7) the amount of direction provided by the inventor and the existence of working examples: Applicants appear to have made a single embodiment with a described structure; their elected species (p84, 1st paragraph), although mention of synthesis and testing of other compounds is described (example 6, p89, 1st paragraph). Testing appears to only have used a single variant of SARS-CoV-2. There is mention of treating RNA viruses, but no examples or discussion beyond the bare mention.
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure: Applicants are claiming a method of treating SARS CoV2, all coronaviruses, or all RNA viruses, depending on the claim. Dinata et al teaches that SARS CoV2 rapidly mutates to generate vaccine and drug resistance, and Guo et al shows that a single mutation will have a high probability of abrogating binding. This clearly shows that there exists a genus of SARS CoV2 mutants that will be resistant to treatment with any given embodiment of the invention. If a single mutation is likely to abrogate activity, a person of skill in the art would reasonably expect that evolutionally more distant viruses would be unlikely to be susceptible to the claimed therapy, especially with viruses, such as the measles virus, where the protein being targeted is not even present. Thus, it will take undue experimentation to use the method as claimed.
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.
Claim 5 is 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 5 lists proteins the first moiety can bind to, but the different groups of proteins are connected by the conjunction “and.” This makes it unclear if the construct has to bind to any one of these proteins or all of them.
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.
Claims 1-5, 48, 51, 53, 54, and 79-81 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Liu, Yuzhi et al. “The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020.” European journal of medicinal chemistry vol. 206 (2020): 112711; made available online 6 August 2020) in view of Ratia et al. (Ratia, Kiira et al. “A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication.” Proceedings of the National Academy of Sciences of the United States of America vol. 105,42 (2008): 16119-24) and US 20190300576 A1, hereinafter Pentelute et al. (filed 2018-11-30 and published 2019-10-03), and in further view of Hines et al. (Hines, John et al. “MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53.” Cancer research vol. 79,1 (2019): 251-262) and US 9250238 B2, hereinafter Low et al., as evidenced by Uldrijan et al. (Uldrijan, Stjepan et al. “An essential function of the extreme C-terminus of MDM2 can be provided by MDMX.” The EMBO journal vol. 26,1 (2007): 102-12).
With regard to claims 1 and 2, Liu et al. teach proteolytic targeting chimaera (PROTAC) technology that can be used in anti-coronaviral drugs that induce the intracellular degradation of functional non-structural proteins of exogenous viruses (see page 16, paragraph 1). They teach the use of a bifunctional small molecule that links a target protein and an E3 ligase in the cell such that the target protein is ubiquitinated, and the ubiquitinated protein is then recognized by the proteasome, which leads to degradation of the protein (see page 16, paragraph 1). They further teach that only the NS3/4A protease degrader DGY-08-097 of hepatitis virus has been reported in use against degradation of foreign proteins, and its antiviral activity and resistance characteristics are significantly superior to those of the traditional drugs, which they use as a motivation to apply this technology to coronaviral proteases (see page 16, paragraph 1). Thus, they propose that existing 3CLpro (a coronaviral protease) inhibitors can be combined with PROTAC technology to develop coronavirus 3CLpro PROTACs, which can lead to multiple rounds of 3CLpro degradation and would avoid the intracellular accumulation of 3CLpro in infected cells, completely blocking the biological function of coronavirus 3CLpro and its downstream viral proteins and inhibiting the assembly and replication of the coronavirus in infected cells (see page 16, paragraph 1). Within the bifunctional chimeras, Liu et al. also teach the use of inhibitors of coronaviral proteases, specifically 3CLpro, with piperidine, 3-pyridyl, or triazole moieties on account of benefits like their ability in interact with numerous classes of proteins (see page 6, paragraph 4 and page 8, paragraph 4). As seen in Figure 20 of Liu et al., the PROTAC functional domains are directly attached, seeing as the single PROTAC connects both the ligase and the 3CLpro (see Figure 20, page 15). Although Liu et al. teach the chimera discussed above wherein a first and second moiety can be joined together to target and ubiquitinate coronaviral proteases, they do not teach that the second moiety can be the HDM2-targeting moiety SEQ ID NO: 1 of the instant application. Here, Pentelute et al. claim that the peptide of SEQ ID NO: 40 of the reference application, which is almost identical to SEQ ID NO: 1 of the instant application (see claims 1, 12, and 40), save that it has Dap residues instead of a crosslinker. However, the reference discusses stapling with similar sequences in those positions (note paragraphs 10-12, for example), making that an obvious variant. The reference motivates using this sequence by teaching that it can be used to disrupt p53-MDM2 interaction when used in a pharmaceutical composition (see claims 1, 12, and 40). This is a motivation for the use of the peptide in disease treatment because p53 is an essential regulator of disease response (see [0442]). Specifically, as stresses are imposed on a cell, p53 is believed to orchestrate a response that leads to either cell-cycle arrest and DNA repair or programmed cell death (see [0442]). Here, it is worth noting that, according to Uldrijan et al., MDM2 and HDM2 are different names for the name ubiquitin ligase that targets p53 (see Abstract and page 102, paragraph 2). Seeing as p53 can be altered by MDM2, if MDM2 is intercepted by MDM2-targeting moieties like those taught in Pentelute et al., suppression of p53 can be prevented, maintaining normal cell responses to stressors (see [0442-0443]). This provides a clear motivation for the use of MDM2-targeting moieties in disease treatment given the broad role of p53 as an important regulator of cell death in response to disease. Pentelute et al. do not, however, incorporate this MDM2 moiety into a PROTAC chimera like that of Liu et al.
Although Pentelute et al. do not explicitly claim that the aforementioned sequence is used in a PROTAC like that of Liu et al., Hines et al. teach that the use of MDM2-binding moieties in PROTACs is well-known in the art (see page 3, paragraph 3). Specifically, they teach that the first all-small molecule PROTAC included recruitment of MDM2 (see page 3, paragraph 3), and that MDM2 can be used for nanomolar-potency PROTAC mediated target degradation, as it retains the p53-stabilizing activity of the parent molecule, allowing a MDM2-recruiting PROTAC to be more active against disease (see page 3, paragraph 4). Here, Hines et al. provide a clear motivation for targeting MDM2 in PROTACs because of their interaction with p53, and Pentelute et al. teach MDM2-p53-targeting peptides that modulate MDM2-p53 activity. As discussed above, given the clear motivations to use SEQ ID NO: 40 of Pentelute et al. (SEQ ID NO: 1 of the instant application) to target MDM2-p53 interaction because of the role of p53 in disease-related cell death, as well as the clear motivation to use MDM2-targeting moieties in PROTACs recited by Hines et al., it would have been obvious to one having ordinary skill in the art prior to the effective filing date of the instant application to combine the references to use SEQ ID NO: 1 of the instant application in a PROTAC chimera like that of Liu et al.
With regard to claim 3, Liu et al. teach the chimera discussed above, but they do not teach the use of a linker between the moieties of the chimera. Here, Low et al. teach a linker comprising the linker structure of Fig. 7 of the instant application (see columns 103 and 104, Scheme 11). Low et al. motivate the use of linkers such as this on account of the fact that their linker is a bishydrazide, and bishydrazides can be useful as chelating agents or as supramolecular recognition motifs (see column 22, lines 17-18). Moreover, they are often used to link polymers or biopolymers, and they found benefits like an ability to be selectively monofunctionalized (see column 22, lines 20-27). They further teach that their linkers can be useful in pathogen detection within the context of their invention (see column 29, lines 21-23). These benefits provide clear motivations to combine the references and use the linkers of the invention of Low et al. in anti-pathogen treatments. As such it would have been obvious to one having ordinary skill prior to the effective filing date of the instant application to combine the references and use the linkers of the invention of Low et al. in anti-pathogen treatments like the chimera of Liu et al.
With regard to claims 5 and 79, Liu et al. teach the chimera discussed above. Although Liu et al. do not explicitly teach inhibiting PLpro, they do teach inhibiting 3CLpro, another coronaviral protease, and they also teach the observation that key 3CLpro inhibitors, specifically tanshinone-type diterpenes, are selective inhibitors of SARS-CoV 3CLpro and PLpro (see page 13, paragraph 2). Given that tanshinone-type diterpenes are identified as having advantages in selectively inhibiting SARS-CoV 3CLpro, there is a clear motivation to choose tanshinone-type diterpenes compounds as the 3CLpro inhibitor in PROTACs (see page 13, paragraph 2). Seeing as there is a clear motivation to use said inhibitors, and since these tanshinone-type diterpenes are also known selectively inhibit PLpro, it would have been obvious to one having ordinary skill in the art prior to the effective filing date of the instant application to use PLpro inhibitors like tanshinone-type diterpenes in PROTACs, thereby targeting PLpro (see page 13, paragraph 2). This does not, however, provide a motivation for the use of GRL-0617 to target PLpro in particular, nor does it necessarily motivate inhibiting PLpro in the absence of 3CLpro inhibitors.
Although Liu et al. teach the broad motivation to use a PLpro inhibitor in the chimera of Liu et al. discussed above, they do not teach the use of GRL-0617 as the Plpro inhibitor. Here, Ratia et al. teach that GRL-0617 is a potent inhibitor of PLpro, and Ratia et al. motivate its use on account of the fact that it has no associated cytotoxicity and has a unique mode of inhibition that shuts down catalysis at the PLpro active site (see Abstract). Moreover, Ratia et al. argue that the aforementioned benefits of using GRL-0617 make PLpro a viable target for the development of antivirals directed against SARS-CoV because potent noncovalent cysteine protease inhibitors can be developed with specificity directed toward pathogenic deubiquitinating enzymes without inhibiting host deubiquitinating enzymes (see Abstract), further motivating the use of PLpro inhibitors in antivirals targeting SARS-CoV replication. Beyond this, they also motivate the use of PLpro inhibitors on account of the fact that PLpro and 3CLpro function in the same way, specifically catalyzing their own release and that of the other nsps from the polyprotein, thereby initiating virus-mediated RNA replication (see page 16119, paragraph 6). They particularly motivate PLpro inhibitors in the place of 3CLpro inhibitors because, despite numerous studies, potent antivirals that directly target 3CLpro have yet to be developed, whereas the study of Ratia et al. clearly establishes potent inhibitors of PLpro, including GRL-0617 (see 16120, paragraph 4). Given this clear motivation to use GLR-0617 as the targeting moiety for PLpro in SARS-CoV antivirals, it would have been obvious to one having ordinary skill prior to the effective filing date of the instant application to combine the references and choose a GRL-0617 PLpro inhibitor when choosing a SARS-CoV protease target in a chimera like that taught in Liu et al. because of its potent inhibitory properties and lack of cytotoxicity.
Liu et al. and Ratia et al. provide clear motivations for targeting PLpro with the first moiety (see Liu et al. page 13, paragraph 2 and Ratia et al. page 16119, paragraph 6 and 16120, paragraph 4). Further, as discussed above, Ratia et al. provide a clear motivation for using GRL-0617 (see Abstract). Given the reasoning discussed above, it would have been obvious to one having ordinary skill in the art prior to the effective filing date of the instant application to combine the references to target PLpro with the chimera of Liu et al.
With regard to claim 22, as discussed above, Pentelute et al. provide a clear motivation for using the MDM2 (HDM2)-targeting sequence of SEQ ID NO: 1 of the instant application (see claims 1, 12, and 40 and SEQ ID NO: 40 of the reference). Given the reasoning provided above, it would have been obvious to one having ordinary skill in the art prior to the effective filing date of the instant application to combine the aforementioned references and use this HDM2-targeting moiety in an anti-pathogen chimera like that of Liu et al.
With regard to claim 48, Pentelute et al. teach the use of pharmaceutically acceptable carriers in conjunction with the peptides of their invention, including HDM2-targeting moieties (see Pentetule et al. [0422], [0424], and [0426-0427]). As discussed above, there is a clear motivation to combine the aforementioned references to teach the chimera, and given this motivation, it would have been obvious to use the chimera of Liu et al. in combination with the peptide sequence SEQ ID NO 40 of Pentelute et al. and a pharmaceutically acceptable carrier (see Pentetule et al. [0422], [0424], and [0426-0427]).
With regard to claim 65, Liu et al. teach the PROTAC discussed above. Although the references of Liu et al., Ratia et al., Pentelute et al., and Hines et al. provide clear motivations for linking GRL-0617 and the sequence of SEQ ID NO: 1 of the instant application in a chimera like that of Liu et al., they do not explicitly teach the linker depicted in Fig. 7 of the instant application. As discussed above, Low et al. teach a linker comprising the linker structure of Fig. 7 of the instant application (see columns 103 and 104, Scheme 11). Low et al. motivate the use of linkers such as this on account of the fact that their linker is a bishydrazide, and bishydrazides can be useful as chelating agents or as supramolecular recognition motifs (see column 22, lines 17-18). Moreover, they are often used to link polymers or biopolymers, and they found benefits like an ability to be selectively monofunctionalized (see column 22, lines 20-27). They further teach that their linkers can be useful in pathogen detection within the context of their invention (see column 29, lines 21-23). These benefits provide clear motivations to combine the references and use the linkers of the invention of Low et al. in anti-pathogen treatments. As such it would have been obvious to one having ordinary skill prior to the effective filing date of the instant application to combine the references and use the linkers of the invention of Low et al. in anti-pathogen treatments like the chimera of Liu et al.
With regard to claim 66, Pentelute et al. teach the use of pharmaceutically acceptable carriers in conjunction with the peptides of their invention, including HDM2-targeting moieties (see Pentetule et al. [0422], [0424], and [0426-0427]). As discussed above, there is a clear motivation to combine the references, and given this motivation, it would have been obvious to use the chimera of Liu et al. in combination with the peptide sequence SEQ ID NO 40 of Pentelute et al. and a pharmaceutically acceptable carrier (see Pentetule et al. [0422], [0424], and [0426-0427]).
With regard to claims 80 and 81, as discussed above, Pentelute et al. claim that the peptide of SEQ ID NO: 40 of the reference application, which is identical to SEQ ID NO: 1 of the instant application (see claims 1, 12, and 40). They motivate its use by teaching that it can be used to disrupt p53-MDM2 interaction when used in a pharmaceutical composition (see claims 1, 12, and 40). This is a motivation for the use of this HDM2-targeting peptide in disease treatment because p53 is an essential regulator of disease response because, as stresses are imposed on a cell, it is believed to orchestrate a response that leads to either cell-cycle arrest and DNA repair or programmed cell death (see [0442]). Seeing as p53 can be altered by MDM2, if MDM2 is intercepted by MDM2-targeting moieties like those taught in Pentelute et al., suppression of p53 can be prevented, maintaining normal cell responses to stressors (see [0442-0443]). This provides a clear motivation for the use of MDM2-targeting moieties in disease treatment given the broad role of p53 as a regulator of cell death in response to disease. Again, as discussed above, Hines et al. teach that the use of MDM2-binding moieties in PROTACs is well-known in the art (see page 3, paragraph 3). Given the reasoning to combine the references provided above, it would have been obvious to one having ordinary skill in the art prior to the effective filing date of the instant application to combine the references and use the sequence of Pentelute et al. in a chimera like that of Liu et al.
Conclusion
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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