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 .
Priority
The instant application, filed 01/05/2024, is a 371 filing of PCT/EP2022/069087, filed 07/08/2022, which claims foreign priority to EP21184516.9, filed 07/08/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55.
Amendments and Claim Status
The amendment filed on 01/05/2024 is acknowledged and entered.
Claims 1-15 are amended;
Claims 16 and 17 are added.
Claims 1-17 are pending and are under prosecution.
Information Disclosure Statement
The Information Disclosure Statement filed on 06/05/2024 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the information disclosure statement is considered.
Restriction/Election
Applicant’s election without traverse of Group I in the reply filed on 06/30/2026 is acknowledged. Furthermore, Applicant’s election of the following specific species is also acknowledged:
Species A: Applicant has elected compound 23 as a species of Formula (I)
Species B: Applicant has elected respiratory syncytial virus (RSV) as a species of a virus
In accordance with MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
As per MPEP § 803.02, the Examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species (Figure 1) does not make a contribution over the prior art of record.
Figure 1. Elected Species
PNG
media_image1.png
454
535
media_image1.png
Greyscale
Figure 1. Compound 23: N-[3-[(3,4-dihydroxybenzoyl)amino]-2-[[(3,4-dihydroxybenzoyl)amino]methyl]-2-methyl-propyl]-3,4-dihydroxy-benzamide
With regard to the right for rejoinder of the withdrawn claims, pursuant to MPEP § 821.04, in order to be eligible for rejoinder, a claim to a nonelected invention must depend from, or otherwise require all the limitations of an allowable claim. Applicant is further advised that rejoinder under MPEP §821.04 (b) operates only in one direction: it permits withdrawn process claims to be rejoined once an elected product claim is found allowable. It does not, however, provide a basis for rejoining withdrawn product claims where, as in the instant case, the process is the elected invention. Accordingly, the withdrawn product claims are no longer eligible for rejoinder within the instant application.
Status of Claims
Claims 1-17 are pending in the instant application. Claims 8 and 14-17 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Therefore, claims 1-7 and 9-13 read on an elected invention and species and are therefore under consideration in the instant application.
Drawings
The drawings filed on 01/05/2024 are objected to under 37 CFR § 1.83(a) for the following reasons:
The different data types are indistinguishable in Figures 1-6. The figures lack a figure key to describe the different data types. The figures must be remade with a figure key describing the different types of data found in the figures.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR § 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR § 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1 and 9 are objected to for including duplicate limitations:
Claims 1 and 9 recite wherein Z1 is defined by a Markush group which contains both CH(R) and CH(R1) as substituents. The claim further recites wherein
R is selected from OH, optionally substituted C1-6 alkyl, NR7R8, and
PNG
media_image2.png
150
192
media_image2.png
Greyscale
R1 is selected from OH, optionally substituted C1-6 alkyl, and NR7R8;
These limitations result in the duplicate limitations wherein Z1 is CH substituted with optionally substituted C1-6 alkyl, and NR7R8, which is unnecessarily redundant. In order to overcome the objection, Applicant may amend the claims (e.g., to remove either CH(R) or CH(R1); amend the limitations of either R or R1; etc) to remove the duplicate limitations.
Claims 1 and 9 further recite wherein R2, R3, R4, R5, and R6 are defined by a Markush group which contains both OH and OR7 as substituents. Claim 1 subsequently recites wherein:
R7 is defined by a Markush group which contains H
These limitations result in duplicate limitations wherein R2, R3, R4, R5, and R6 are OH, which is unnecessarily redundant. In order to overcome the objection, Applicant may amend the claims (e.g., amend the limitations of either R2, R3, R4, R5, and R6 ; etc) to remove the duplicate limitations.
Improper Markush Rejection
Claims 1-7 and 9-13 are rejected on the basis of containing an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Members of a Markush group share a "single structural similarity" when they belong to the same recognized physical or chemical class or to the same art-recognized class. A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted for the other, with the expectation that the same intended result would be achieved. Such is not the case in the instant claims because none of the rings in each of the core structures of each of the general formulas are obvious variants nor could they be substituted for one another with a reasonable expectation of similar results.
Improper Markush Grouping of Viral Taxa
The Markush grouping of the viral taxa is improper because the alternatives defined by the Markush grouping do not share a single structural similarity. Claim 1 recites a Markush group of viral taxa: Alphaherpesvirinae; Monodnaviria; Negarnaviricota; Pisuviricota; and Flavivirus. The specification of the instant disclosure (Table 1, reproduced below) establishes that these taxa do not share a single structural feature essential to the claimed antiviral utility.
PNG
media_image3.png
432
672
media_image3.png
Greyscale
Firstly, Table 1 shows that the five lineages claimed differ in genome composition. For example, Alphaherpesvirinae have double-stranded DNA (dsDNA) genomes, while Monodnaviria have single-stranded DNA (ssDNA) genomes, and Negarnaviricota have single-stranded RNA (ssRNA)(-) genomes while Pisuviricota; and Flavivirus have ssRNA(+) genomes. The genotype dictates replication strategy, polymerase use, and the entire molecular biology of the infection. Viruses with different genotypes of no concern replication machinery that a single compound class could universally target.
Table 1 further shows that the five lineages belong to three separate realms: Duplodnaviria (Alphaherpesvirinae), Monodnaviria (HPV), and Riboviria (RSV, SARS-CoV-2, Zika). As the Applicant’s own specification demonstrates, these realms represent the most basal evolutionary divergence among viruses. No structural or functional feature is conserved across the three realms.
Table 1 also reveals that the members of the instantly claimed Markush grouping are recited at inconsistent taxonomic ranks. Alphaherpesvirinae is a subfamily. Monodnaviria is a realm. Negarnaviricota and Pisuviricota are phyla. Flavivirus is a genus. Monodnaviria encompasses thousands of species across multiple phyla, while Flavivirus contains tens of species within a single genus. The grouping treats a realm and a genus as equivalent alternatives, although they differ in scope by orders of magnitude.
Furthermore, Table 1 implicitly shows that the Markush group includes both enveloped and non-enveloped viruses. For example, HPV-16, the tested representative of Monodnaviria is a non-enveloped virus, while the other four tested representatives (HSV-1, RSV, SARS-CoV-2, Zika) are enveloped. The specification proposes that the compounds asked directly on the viral particle (page 8, lines 20-21), and describe experiments supporting a virion-directed mechanism (pages 46-48). If the compounds indeed act through interaction with viral envelope or surface, there is no structural basis for grouping enveloped and non-enveloped viruses as members of a single Markush group.
Finally, the specification’s own data demonstrates that compound activity is not consistent across the claimed viruses. For example, Table 2 reports RSV IC50 values for 22 of the 24 tested compounds, but SARS-CoV-2 IC50 values for only 1 of the 24 compounds. The remaining compounds were never tested against SARS-CoV-2, and no IC50 values for any of the remaining preferred viruses, such as HPV, HSV-1 or Zika virus are reported in Table 2 for any compound. Figure 8 shows that compounds 16 and 18 were tested against HPV, HSV-1, and Zika, but only quantitatively, and only for these 2 compounds out of 24. Figure 9 shows SARS-CoV-2 cell culture data for only compounds 18 and 23. The specification therefore does not establish that any single compound is acted against all five claimed viral lineages, and the vast majority of compounds were tested against only one virus (RSV). The selected testing undermines any inference that the compounds share a common mechanism operated across the instantly claimed taxa.
Improper Markush Grouping of the compounds of Formula (I)
PNG
media_image4.png
152
399
media_image4.png
Greyscale
The Markush grouping of the compounds of Formula (I) are improper because the alternatives defined by the Markush grouping do not share a single structural similarity. The cited claims of the instant application claim a compound represented by the following general formula (left) recited in claim 1 as Formula (I), which comprises a wide range of substituents that substantially affect the core structure and activity of the instantly claimed compounds.
For example, according to the instant claims, Y varies between ester linkages (compounds 1-13), and amide linkages (14-24)—functional groups with fundamentally different hydrogen bonding capacity, and hydrolytic stability. The specification itself (Figure 10) demonstrates that compound 23 is stable, while the ester reference 4,5-DCQA degrades. Furthermore, Z1 varies from O, to CH2, to CR(R1), producing scaffolds ranging from acyclic linear chains (compound 3) to branched neopentyl cores (compound 4), to ether linkers (compound 5), to a cyclohexyl ring as a bridging unit (compound 6), (see portion of table 2 reproduced below). Compound 5’s measured inactivity despite the identical hydroxylation pattern to the active compounds 3, 4, and 6, confirms that the aromatic head alone is not sufficient for activity. Finally, L Stands linear alkenyl (compound 3), branched alkenyl (compound 4), polyglycol (compound 5), and ring-fused carbocycle (compound 6) linkers. These are fundamentally different topologies which do not share a singular structural similarity, and affect antiviral function. According to the specification, the scaffold itself determines whether a compound is antiviral. Nevertheless, Formula (I) encompasses all of these disparate architectures within the instantly claimed method of treatment. Beyond the results of the specification, there is no identification of which structural features of the
PNG
media_image5.png
539
676
media_image5.png
Greyscale
PNG
media_image6.png
20
328
media_image6.png
Greyscale
instantly claimed compounds are central to the utility method instantly claimed.
PNG
media_image7.png
162
276
media_image7.png
Greyscale
PNG
media_image8.png
166
283
media_image8.png
Greyscale
Table 2 also shows that antiviral activity is highly sensitive to the compounds’ ring substitution patterns. For example, compounds with sparse hydroxylation (e.g., compound 19, right, bearing only 3 hydroxy in total) shows no measurable RSV IC50 values, and cell viability > 80,000 nM. Further, compounds with methylenedioxy groups replacing free hydroxyl groups (e.g., compound 21, left) eliminates the free catechol diols groups shared amongst the active compounds, are similarly inactive. Yet, both compounds fall within Formula (I), because claim 1 requires only that “at least one occurrence of R2, R3, R4, R5, or R6 is OH, and/or wherein at least two occurrences of R2, R3, R4, R5, or R6 form together part of an optionally substituted 4- to 8-membered heterocyclic ring containing O.”
In summary, the instant claims feature a doubly improper Markush grouping. A broad group of structurally diverse compounds is claimed to treat a broad group of structurally diverse viruses. The specification demonstrates neither a common structural feature among the viruses that the compounds can target, nor a common structural feature amongst the active and inactive compounds which would predict which members of Formula (I) would be effective. Applicant’s own data shows that activity depends on hydroxylation patterns (compounds 10, 11, 18, and 23, all bearing 3,4-dihydroxy or 3,4,5-trihydroxy groups on multiple rings). Furthermore, the specification demonstrates that linker types affect the stability of the compounds (amides outperform esters, Figure 10). Nevertheless, the mark whose group captures inactive compounds alongside active compounds within the instantly claimed method.
Accordingly, the Markush groupings of claims 1-7 and 9-13 are deemed improper because neither the viral taxa nor the compound members share a single structural feature essential to the claimed utility.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 U.S.C. § 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.
Claims 1-7 and 9-13 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.
Claims 17 and 9-13 of the instant application are drawn to compounds having following substituents:
L is, independently for each occurrence, optionally substituted C1-6 alkylene, wherein carbon atoms from two L groups can optionally form, together with Z1, part of an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring;
R1 is selected from OH, optionally substituted C1-6 alkyl, and NR7R8;
R2 is H, halogen, OH, CN, NR7R8, C(O)NR7R8, and OR7;
R3 is H, halogen, OH, CN, NR7R8, C(O)NR7R8, and OR7;
R4 is H, halogen, OH, CN, NR7R8, C(O)NR7R8, and OR7;
R5 is H, halogen, OH, CN, NR7R8, C(O)NR7R8, and OR7;
R6 is H, halogen, OH, CN, NR7R8, C(O)NR7R8, and OR7;
R7 is H and optionally substituted C1-6 alkyl;
R8 is H and optionally substituted C1-6 alkyl
35 U.S.C. § 112(a) and the first paragraph of pre-AIA 35 U.S.C. § 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111,1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description"). The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert, denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Bees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); EliLilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm.,927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). An application specification may show actual reduction to practice by describing testing of the claimed invention.
In the present case, the important factors leading to a conclusion of inadequate written description is the lack of a representative number of species that characterizes the entire claimed genus and accounts for variations between species of the genus.
In the instant specification, there is no disclosure of compounds having the following claimed substituents:
L as wherein carbon atoms from two L groups can optionally form, together with Z1, part of an optionally substituted 4- to 5- or 7- to 8-membered carbocyclic or 4- to 8-membered heterocyclic ring;
R1 as selected from OH, optionally substituted C2-6 alkyl, and NR7R8;
R2 as halogen, CN, NR7R8, C(O)NR7R8, and OR7;
R3 as halogen, CN, NR7R8, C(O)NR7R8, and OR7;
R4 as halogen, CN, NR7R8, C(O)NR7R8, and OR7;
R5 as halogen, CN, NR7R8, C(O)NR7R8, and OR7;
R6 as halogen, CN, NR7R8, C(O)NR7R8, and OR7;
R7 is H;
R8 is H;
The instant specification (pages 41-46) teaches compounds which are characterized as having only the following substituents:
L is unsubstituted C1-6 alkylene, wherein carbon atoms from two L groups can optionally form, together with Z1, part of an optionally substituted 6-membered carbocyclic
R1 is CH3
R2 is H and OH;
R3 is H and OH;
R4 is H and OH;
R5 is H and OH;
R6 is H and OH;
R7 is H;
R8 is H;
Therefore, the methods and compounds described in the instant specification detail only a limited number of the total substituents claimed (see substituents 1-9, above). All working examples presented in the instant specification are related to the compounds containing a fraction of the total claimed substituents (see substituents 19-27, above).
There are no working examples in the instant specification for the wide range of substituents claimed, but for which evidence of possession has not been provided (see substituents 10-18, above). Thus, the instant specification does not provide any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application.
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F. 3d 1565, 1572, 41 USPQ2d 1961, 1966(1997); In re Gosteli, 872 F.2d 1008, 1012,10 USPQ2d 1614, 1618 (Fed Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.") Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For example, disclosure of only a method of making the invention and the function may not be sufficient to support a product claim other than a product-by-process claim. See, e.g., Fiers v. Revel, 984 F.2d at 1169, 25 USPQ2d at 1605; Amgen, 927 F.2d at 1206, 18 USPQ2d at 1021.
Thus, since Applicant has not described in adequate detail methods to synthesize compounds containing the claimed substituents, or provided evidence that said compounds have been characterized, or that they exist, an ordinary skilled artisan could not completely envisage Applicants’ invention. Moreover, it is clear that the written description requirement has not been met since Applicant has not provided any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application. Thus, claim 1-13 of the instant application are not supported by the instant specification and thus a rejection under 35 U.S.C. § 112 (a) for failing to comply with the written description requirement is proper.
Claims 1-7 and 9-13 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 a viral infection caused by respiratory syncytial virus (RSV), it does not reasonably provide enablement for a method of treating a viral infection caused by a virus belonging to a taxon selected from Alphaherpesvirinae; Monodnaviria; Negarnaviricota; Pisuviricota; and Flavivirus comprising the administration of a compound of Formula (I). The specification does not provide sufficient information to support the instant claims.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention;
(2) the state of the prior art;
(3) the relative skill of those in the art;
(4) the predictability or unpredictability of the art;
(5) the breadth of the claims;
(6) the amount of direction or guidance presented;
(7) the presence or absence of working examples; and
(8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 1-7 and 9-13 of the instant application are drawn to a method of treating a viral infection caused by a virus belonging to a taxon selected from Alphaherpesvirinae; Monodnaviria; Negarnaviricota; Pisuviricota; and Flavivirus comprising the administration of a compound of Formula (I).
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that a broad range of compounds can be used to treat a large range of diverse viral taxa. The recited taxa span three viral realms, and encompass both DNA and RNA genome compositions, and both enveloped and non-enveloped viruses (Table 1). Furthermore, the compounds administered within the method are structurally diverse.
State of the Prior Art: There are no art-recognized methods that could be used to establish that the instantly claimed viral infections can be commonly addressed using the claimed therapeutic method comprising the administration of a singular compound class. Additionally, the disclosure does not discuss, or demonstrate through working examples, a successful method of treatment using the vast range claimed compounds against the large range of viral taxa members.
Regarding common viral taxonomy, and the structural divergence of the claimed taxa, the International Committee on Taxonomy of Viruses Executive Committee (Nat Microbio Vol 5, pages 668-674, published April 27, 2020), hereinafter ICTVEC, partitions the virosphere into 15 hierarchical ranks (Figure 1, ICTVEC). The “realm” is the highest rank, representing the most ancient and fundamental evolutionary divergences among all known viruses (pages 668). ICTVEC teaches that viruses classified in different realms share no common ancestor within the virosphere and possess no common structural or functional features beyond the use of nucleic acids as genetic material (pages 669 and 670, Figure 2). ICTVEC teaches that the expanded hierarchy is necessary because prior taxonomy, limited to five ranks from order to species, could not represent the deepest evolutionary relationships among viruses (pages 668 and 669). Using HSV-1, SARS coronavirus, and Ebola viruses as examples, ICTVEC demonstrates that these viruses occupy entirely separate branches of the hierarchy at every rank above “order” (Table 1). The teachings of ICTVEC establish that the five taxa recited in the instant claims occupy the deepest evolutionary divergences in the virosphere, with no common structural or functional target that would provide a basis for predicting that a single compound class could treat infections caused by members of all five distinct lineages.
Predictability/Unpredictability in the Art: The pharmaceutical arts, particularly the treatment of viral diseases and antiviral drug development, are well-recognized as highly unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. The courts have upheld that in unpredictable arts, a greater degree of specificity is required to satisfy the enablement requirement.
Viral infections comprise a heterogeneous group of diseases with distinct molecular drivers, infectious mechanisms, implicated signaling pathways, and therapeutic responses. Activity against one virus does not protect activity against another, absent shared a molecular target or mechanism of infection. The instant specification identifies no such target, such as a conserved surface protein or common capsid architecture. As such, a person of ordinary skill in the art would recognize the treatment of a large range of viral infections which do not share a common molecular target or generalized viral structure would not reliably predict therapeutic efficacy across different sources of infection. The translation of infection rate or cell line activity into an effective antiviral treatment depends on numerous factors, including infectious mechanism, compensatory signaling mechanisms, tissue-specific effects, toxicity, and therapeutic window, none of which are addressed in a comprehensive or predictive manner in the instant specification.
Guidance of the Specification/Working Examples: Applicant has only provided working examples suggesting that compounds of Formula (I) may definitively treat RSV. Figures 1-6 present dose-response curves exclusively for RSV where all 22 compounds with measurable activity were tested against only RSV. Table 2 reports quantitative IC50 values against RSV for these compounds, but provides SARS-CoV-2 IC50 values for only a singular compound (compound 23, the elected species). No quantitative IC50 values against HPV, HSV-1, Zika, or any other members of the recited taxa are reported anywhere within the disclosure. Figure 8 shows only two compounds, compounds 16 and 18, tested against HPV, HSV-1, and Zika virus, but only at a handful of concentrations, and not in full dose-response curves. The mechanism of action experiment in Figure 7 and the stability study of Figure 10 were performed exclusively with RSV. Thus, the specification fails to provide sufficient evidence in support of the broad treatment of all viral taxa with the full range of the compounds of Formula (I).
The Quantity of Experimentation Required: In order to practice Applicant’s invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the large range of untested members of viral taxa can be treated by the administration of the compounds as claimed. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome. Such experimentation would necessarily include virus-specific validation of therapeutic efficacy, optimization of dosing regimens, assessment of toxicity and side effect profiles, and identification of responsive versus nonresponsive virus subtypes. The specification provides only limited in vitro data demonstrating activity in RSV for a limited subset of the compounds of Formula (I) recited in the claims. Accordingly, determining which viral taxa may be effectively treated would require extensive, individualized experimentation, amounting to undue burden.
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. Accordingly, a method of treating a viral infection caused by a virus belonging to a taxon selected from Alphaherpesvirinae; Monodnaviria; Negarnaviricota; Pisuviricota; and Flavivirus comprising the administration of a compound of Formula (I) is not enabled by the instant specification.
Claim Rejections - 35 U.S.C. § 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 3 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 3 recites the broad recitation “L is, independently for each occurrence, C1-6 alkylene,” and the claim also recites “preferably linear or branched C1, C2, C3, C4, C5 or C5 alkylene, or methylene,” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 U.S.C. § 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.
Claims 1-3 and 6 and 7 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Rivero-Buceta et al., (European Journal of Medicinal Chemistry, Volume 92, pages 656-671, published January 17, 2015, cited on applicant IDS filed 06/05/2026), hereinafter Rivero-Buceta.
The instant claims are drawn to method for treating a viral infection caused by a virus belonging to a taxon selected from Alphaherpesvirinae, Monodnaviria, Negarnaviricota, Pisuviricota, and Flavivirus, comprising the administration of a compound of Formula (I).
Rivero-Buceta teaches compound 10 (Scheme 2), also known as CAS Registry Number: RN 117446-40-9. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 117446-40-9. Entered STN: 11 Nov 1988]. Rivero-Buceta teaches compound 10 and a myriad of other compounds which read on the instant claims, used as inhibitors of Hepatitis C Virus (HCV) in the range of other viruses (Table 2). Rivero-Buceta teaches wherein HCV belongs to the family of Flaviviridae (page 656, see instant claims 1 and 2).
Compound 10 anticipates a compound of Formula (I) (claims 1, 3, and 6-8) wherein,
Figure 2. Structural comparison of instantly claimed Formula (I) and prior art compound
PNG
media_image9.png
221
949
media_image9.png
Greyscale
Figure 2. a) Instantly claimed Formula (I); b) CAS Registry Number: RN 117446-40-9;
R2 and R6 are H
R3, R4, and R5 are OH
Y is O
L is C3 and C4 alkylene
Z1 is CH2
The cited teachings set forth above are individually applied to the claims, and the claims are determined to be anticipated by the prior art.
Applicant is hereby notified that the teachings of the cited art also apply to claim 8 which is presently withdrawn (wherein three of R2, R3, R4, R5, or R6 are OH). Furthermore, several compounds within the disclosure read on the compounds of the instant claims. In any forthcoming amendments, the entirety of the disclosure as it applies to the claim set as a whole should be carefully considered.
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of pre-AIA 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.
Claim 1-7 and 9-13 are rejected under 35 U.S.C. § 103 as being unpatentable over Cheraı̈ti et al. (J OrgMet Chem Volume 575, Issue 1, pages 149-152, published February 22, 1999, cited on applicant IDS filed 06/05/2024), hereinafter Cheraı̈ti, in view of Isaacs et al. (Antimicrob Agents Chemother, Volume 55, pages 5646-5653 published September 26, 2011), hereinafter Isaacs.
The instant claims are drawn to a method for treating a virus elected to be respiratory syncytial virus (RSV) by the administration of a compound of Formula (I), elected to be compound 23 (see Figure 3a).
Cheraı̈ti teaches compound 8 (Scheme 1), also known as CAS Registry Number: RN 222633-33-2. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 222633-33-2 Entered STN: 07 May 1999] (see Figure 3b). Cheraı̈ti teaches wherein compound 8 is the smallest iron chelator (siderophore) known (page 149), later characterizing its iron and gallium complexes. The prior art compound differs from the elected species only in the placement of the hydroxide substituents on the phenyl rings (see circled hydroxides in Figure 3, below).
Figure 3. Structural comparison of elected species and prior art compound
PNG
media_image10.png
402
840
media_image10.png
Greyscale
Figure 3. a) Clected species; b) Cheraı̈ti Compound 10, CAS Registry Number: RN 222633-33-2
In the elected species, the two hydroxides substituents are substituted as 3,4-dihydroxy while in the prior art compound are substituted as 2,3-dihydroxy. This type of structural modification of the position of hydroxy substituents, also known as “ring-walking” is considered to be an obvious modification within the field of drug development. According to MPEP § 2144.08 (II) (A) (4) (c),
If a prior art species or subgenus is structurally similar to that claimed, its disclosure may provide a reason for one of ordinary skill in the art to choose the claimed species or subgenus from the genus, based on the reasonable expectation that structurally similar species usually have similar properties. See, e.g., Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Deuel, 51 F.3d 1552, 1558, 34 USPQ2d 1210, 1214 (Fed. Cir. 1995) ("Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties."
Based on the structural similarities outlined above, the elected species and the prior art compound would be expected to have similar properties. Thus, a person of ordinary skill in the art would have found it obvious to modify the prior art compound to arrive at the elected species.
PNG
media_image11.png
150
401
media_image11.png
Greyscale
Regarding Formula (I) (below), compound 8 reads on the instant claims wherein,
R2, R3 are OH (see instant claims 1, 3, 7, and 9)
R4, R5, and R6 are OH (see instant claims 1, 3, 7, and 9)
Y is NR7 (see instant claims 1, 3, 6, and 9)
R7 is H (see instant claims 1, 3, 6, and 9)
L is C2 alkylene (see instant claims 1, 3, and 9)
Z1 is CHR or CHR1 (see instant claims 1, 3-7, and 9)
R1 or R is CH3 (see instant claims 1, 3-7, and 9)
Cheraı̈ti fails to teach or suggest any antiviral use for compound 8.
The deficiencies of Cheraı̈ti are remedied by Isaacs, who discloses that epigallocatechin gallate (ECGC) and its digallate dimers (i.e., polyphenolic compounds bearing multiple galloyl moieties (page 5647, Figure 1) inactivate a panel of enveloped viruses including RSV (page 5651, Figure 1, see instant claims 1, 2, and 9-13). Isaacs further teaches that the antiviral potency increases with the number of galloyl groups (pages 5648-5650, Figures 2-4). Finally, Isaacs discloses the mechanism of antiviral potency involves direct interaction with viral envelope glycoproteins (see instant claim 13, page 5652, Figure 7).
Regarding the structural similarities of the teachings of Isaacs and the elected species, the compounds feature the familiar ortho-dihydroxy phenyl moieties, and thus are characterized as belonging to the same pharmacophore class: multivalent polyhydroxyl benzamide/ester compounds displaying catechol diols.
A person of ordinary skill in the art would have been motivated to combine the teachings of Cheraı̈ti with the teachings of Isaacs because Isaacs establishes that multivalent polyphenolic compounds bearing galloyl moieties inactivate RSV through direct interaction with viral envelope glycoproteins. The compound taught by Cheraı̈ti presents the same catechol scaffold, has three polyhydroxyl galloyl groups, and belongs to the same recognized class of compounds as that taught by Isaacs. A person of ordinary skill, following the disclosure by Isaacs that antiviral potency increases with the number of galloyl groups (pages 5648-5650, Figures 2-4), would have had a reasonable expectation of success in using the prior art compound, or a structural variant thereof as instantly claimed, to effectively treat enveloped viruses such as RSV as disclosed by Isaacs.
Conclusion
Claims 1 and 9 are objected to.
Claims 1-7 and 9-13 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sophia P. Hirakis whose telephone number is +1 (571) 272-0118. The examiner can normally be reached within the hours of 5:00 am to 5:00pm EST, Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached on +1 (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is +1 (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call +1 (800) 786-9199 (IN USA OR CANADA) or +1 (571) 272-1000.
/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/VALERIE RODRIGUEZ-GARCIA/ Primary Examiner, Art Unit 1621
Prosecution Insights