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 present Application, filed April 26, 2024, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/EP2022/074088, filed August 31, 2022, which claims priority to European Patent Application No. EP21194436.8, filed September 1, 2021, the benefit of which is claimed with an effective priority date of August 31, 2021.
Status of the Claims
In the Preliminary Amendment filed with the national stage entry, claim 19 is canceled and claims 1–18 and 20 are amended. Claims 1–18 and 20 are currently pending.
Information Disclosure Statement
No information disclosure statement has been filed. The nine prior art references cited in the Written Opinion of the International Searching Authority (D1–D9) and the late-cited document WO 2021/170464 are considered as part of the examination record.
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 15-16 are indefinite:
Claims 15-16 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 15 recites the limitation "where Q is a bicyclic condensed ring system of formula Q1 to Q13; where rings Q1 to Q13 carry k substituents…" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. Claim 15 depends from claim 1, and there is no definition of formula Q1-Q13 is in this dependency chain. Claim 16 similarly recites definitions of Q1, Q2, Q5, and Q12, where these moieties exist in a formula that is not recited in the claim 16 dependency chain. These terms would have proper antecedent basis of claim 15 depended from claim 13, rather than from claim 1.
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.
Claims 1–12, 17-18, and 20 fail to comply with the written description requirement:
Claims 1–12, 17-18, and 20 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Specifically, Applicant does not have sufficient support for the very large genus of compounds encompassed by many of the present claims. Many of the claims allow considerable structural breadth at a number of variable moieties and yet, as discussed below, the real examples disclosed in the present application cover only a very small fraction of this structural diversity. As such, claims 1–12, 17-18, and 20 lack sufficient written description support.
The written description requirement is distinct from the enablement requirement; as was first pointed out by the court in In re Ruschig, 379 F.2d 990, 154 USPQ 118 (CCPA 1967), and clarified in Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111 (Fed. Cir. 1991). The issue of whether the claimed subject matter is adequately supported/described by the specification, is a question of fact. Id. at 1563, 19 USPQ2d at 1116.
When considering whether the claimed subject matter complies with the written description requirement, Applicants' disclosure should be read in light of the knowledge possessed by those skilled in the art.
"[T]he disclosure in question must be read in light of the knowledge possessed by those skilled in the art, and that knowledge can be established by affidavits of fact composed by an expert, and by referencing to patents and publications available to the public ... "
In re Lange, 644 F.2d 856, 863, 209 USPQ 288, 294. See also, In re Alton, 76 F.3d 1168, 37 USPQ2d 1578 (Fed. Cir. 1996).
Applicants enjoy the presumption that their patent application is valid and all statements contained therein are accurate; it is the PTO's burden to demonstrate why any of Applicant’s claims should be rejected or why any of Applicant's statements should be doubted.
"it is incumbent upon the Patent Office, whenever a rejection ... is made, to explain why it doubts the truth or accuracy of any statement in a supporting disclosure and to back up assertions of its own with acceptable evidence or reasoning which is inconsistent with the contested statement. Otherwise, there would be no need for the applicant to go to the trouble and expense of supporting his presumptively accurate disclosure."
In re Marzocchi, 439 F.2d 220, 224, 169 USPQ 367, 370. If successful in presenting such evidence and argument, the burden then shifts to the Applicant to provide evidence that would convince one to the contrary.
The Invention in General
Applicants’ invention is directed to malonamide compounds of generic formula I,
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where the variable moieties are as described. The compounds are thought to be useful as herbicides, and a number of working examples are disclosed, having varying herbicidal potency and specificity. The application further discloses herbicidal compositions having a disclosed malonamide along with an auxiliary compound, and methods of controlling unwanted vegetation involving application of the disclosed malonamides.
The Claimed Invention
Claims 1–11 are directed to compounds of formula I, where variable Q is broadly defined as any bicyclic or tricyclic aromatic or partially aromatic condensed (fused) ring system optionally having a variety of in-ring heteroatoms as well variable exocyclic substituents, some of which can be further variably substituted. This definition is fairly open-ended and encompasses an enormous number of possible ring systems, just for the Q moiety alone. With the many possible variations at R1-R4, X, and Y, including possible nested variable substitutions particularly at Y, the number of species encompassed in the genus of claim 1 is astronomically large. Claims 2 further narrows moieties R1 and R4; claims 3-5 narrow R2 and R3; claims 6-9 narrow the genera of X-Y; claim 10 modestly narrows multiple moieties, claims 11-14 narrow the genus of moiety Q, and claims 15-16 narrows the genera of all variable moieties. Claims 16-17 recite a composition having a compound of claim 1 along with an auxiliary compound and potentially another herbicide; while claim 20 recites a method for controlling unwanted vegetation comprising administering a compound of claim 1.
The Supporting Disclosure
Applicants’ supporting disclosure describes the structure and variations of formula (I) (pgs. 2-43. The disclosure further describes preferred embodiments of R1-R4, X, and Y, without specifying Q (Table A, lines 43-123), and lists other preferred embodiments where R1, R4, and Q are constrained but R2-R3 are variable (pgs. 124-167). The disclosure further describes methods for preparing the compounds of formula (I) (pgs. 167-171) and discusses different additional herbicides that can be coadministered with the compound of formula I (pgs. 171-179). The disclosure further describes compositions having a compound of formula (I) with an auxiliary (pgs. 179-185) and methods for treating unwanted vegetation (pgs. 185-194). The disclosure describes Examples, including Synthesis Examples (pgs. 194-200), culminating in Table 1 showing 14 real examples of species of claim 1 Applicant has prepared (pgs. 198-200).
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All working examples have hydrogen at R1, R3, and R4; methyl at R2, a bicyclic ring system with phenyl connected to the malonamide core; and all but one have X-Y as a cyclopentene carboxylate ester. As such, the working examples of the disclosure represent a very small fraction of the sequence space of claim 1, and of the claims generally.
Finally, the disclosure includes Biological Examples, qualitatively describing, with descriptors like “good activity” and “very good activity” the efficacy of most of the fourteen working examples as herbicides against one or more plant species, at different application densities (pgs. 200-202). It is noted that no herbicidal activity is reported for compounds I.5 or I.12. While not stated explicitly, this leads to a tentative inference that these compounds exhibited little-to-no herbicidal activity within the test parameters.
The State of the Art
A number of references that small structural variations in herbicide structural genera can have large effects on herbicidal activity. These references thus instruct that all members of large structural genus of putative herbicides will not necessarily have herbicidal activity, or any broadly shared functional attributes.
For example, the non-patent publication, Design, Synthesis, and Structure-Activity Relationship (SAR) Studies of ketone-isobenzofuranone Hybrid Herbicides, Chem. & Biodivers., 20, art. e202200932, pgs. 1-12 (2022) by Chotsaeng (hereinafter, “Chotsaeng”) describes a structure-activity-relationship study of novel ketone-isobenzofuranone hybrids (Abstract). For example, Chotsaeng shows that, simply through variation of a substituent on a phenyl group of the ketone-isobenzofuranone core, compounds are produced having drastically different degrees of herbicidal activity, ranging from no detected activity to complete plant control (e.g. Figure 1)
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- Above: modified amalgam of Figure 4 and Figure 1B of Chotsaeng, showing location or varied R-group that produces 39 variants species of the genus (left) and herbicidal activity of the species against barnyard grass, showing considerable functional variation as a direct result of R-group variation (right)
As a consequence, Chotsaeng states that
For the first time, all isobenzofuranones were tested for herbicidal activity against Chinese amaranth and barnyard grass. Results from the structure-activity relationships (SAR) clarified that the position and type of substituent were crucial for herbicidal property.
- Chotsaeng, pg. 8, right column, Conclusions, first paragraph (emphasis added)
As such, Chotsaeng teaches, albeit in a different structural context, that even changes in one variable group on an invariant structural core can have dramatic effects on the herbicidal activity of structurally-related compounds.
Similarly, International Patent Application Publication No. WO/1987/005898 to Manning et al. (hereinafter, “Manning”) discloses malonic acid derivatives for use in retarding plant growth (abstract; page 1, lines 1–5). Manning discloses and evaluates the growth retardant activity of over 200 substituted and derivatized malonic acid variants, including a number of substituted malonamic acid variants.
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Above: the malonic acid and malonamic acid cores (left and center) of Manning, and the malonamide core (right) of the instant disclosure.
The structure-activity data in Table J of Manning demonstrates that modest structural variations within these compounds produces substantial variations in growth retardant activity.
For example, Manning discloses Compounds 18, 20, and 22, all malonic acids varying only in the substituents on an aryl group attached to the amide (Table A, page 67).
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Manning reports plant growth retardation activity on a 0-10 scale, with Compounds 18 and 20 having 1 and 2, respectively, whereas Compound 22 has 9, for growth retardation efficacy against snapbeans (Table J, pg. 118). Thus, relatively modest changes in the substituents on a phenyl group, within an otherwise invariant malonamic acid structure, results in a large difference in plant growth retardation efficacy, ranging from negligible retardation to near-complete retardation. Similarly, malonamic acid Compounds 111 and 117, differing only in the presence or absence of a single methyl substituent on a phenyl group, have plant growth retardation ratings of 9 and 2, respectively, against snap beans (pg. 120). These results have been observed to differ for different target plants.
Thus, the art indicates that modest differences in substitution patterns can have dramatic differences in the efficacy of herbicidal and/or plant growth retardation activity, including in compounds structurally similar to those of the present Application. This suggests that, consistent with the results of the present Application, the likelihood that not all species of the very broad genus of instant claim 1 have a common herbicidal activity.
Summary of Written Description Rejection
Claim 1 recites an extremely broad structural genus defined at the Q position by an open-ended ring system definition that encompasses a virtually uncountable number of distinct bicyclic and tricyclic aromatic and partially aromatic ring systems with optional substitution. Similar variability at the Y position expands the claimed genus exponentially, while substituent variation at R1-R4, along with linker variation at position X further increase the very large genus by several more orders of magnitude. In comparison to the enormous genus, fourteen working examples are disclosed. Of significance, the fourteen working examples are highly structurally similar to one another, leaving large swathes of the claimed genus unexemplified. Furthermore, as discussed above, while claim 1 does not recite any functional attributes, a survey of the art suggests the likelihood that the full genus of claim 1 is not encompassed by a common functional thread. This is bolstered by the tentative inference, described above, that two of the fourteen working examples exhibited minimal or no herbicidal activity as tested.
Claims 17-18 and 20 encompass the full structural scope of formula I of claim 1, and while claims 2-12 narrow various aspects of the claimed formula I, they still leave the claimed structural space inordinately large in comparison to the number and structural breadth of the working examples. In short, claims 1–12, 17-18, and 20, in particular, present a claimed genus whose structural breadth is vastly disproportionate to the fourteen exemplified compounds, all of which are clustered in a single narrow structural corner defined by X being a bond, Y being a 5-membered ester-substituted carbocyclic ring, and Q being drawn from a limited set of preferred ring systems. Claims 1-12, 17-18, and 20 fail the written description requirement because they claim overly broad chemical genera that are unsupported by a commensurate disclosure of species spanning the structural breadth of those genera.
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.
Claims 1–5 are obvious over Flohr1:
Claims 1–5 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S. Patent Application Publication No. 2005/0054633 to Flohr et al. (hereinafter, “Flohr1”).
Claim 1 recites a compound of formula I,
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where the variable moieties are as defined.
Flohr1 teaches γ-secretase inhibitors directed to the treatment of Alzheimer’s disease (Abstract) having a formula
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where the variable groups are as defined. For example, R2 can be alkyl or various other groups; R3 and R4 can be hydrogen or alkoxy, and R1 is selected from any of the following four ring systems:
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or
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and
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.
The compound genus of Flohr1 thus overlaps with the compound genus of instant claim 1. Flohr1 further teaches, inter alia, the following three working examples:
(−)-2-methoxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide (Example 68, paragraph [0326]);
N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methoxy-N’-(2,2,3,3,3-pentafluoro-propyl)-malonamide (Example 76, paragraph [0363]); and
2-methoxy-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide (Example 87, paragraph [0398]).
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Each of these is a species of instant formula (I), but they are also the seventh, eighth, and ninth expressly disclaimed species of instant claim 1, and for that reason are not anticipated by claim 1. However, obvious variants of these compounds, according to the teachings of Flohr1, would be compounds of instant claim 1, as well. For example, as noted above, Flohr1 teaches that useful Alzheimer’s therapeutic compounds can have any of the four disclosed ring systems at position R1. It thus would have been obvious to prepare an analog of Flohr1 Example 68 in which the dibenzoazepine ring system is replaced with a monobenzoazepine or dibenzooxepine ring system, and one would have had a reasonable expectation that such a compound would be an effective γ-secretase inhibitor useful for the treatment of Alzheimer’s disease.
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Such obvious variants of the expressly disclosed compounds of Flohr1 would be species of instant claims 1-5, and claims 1-5 are therefore obvious over Flohr1.
Claims 1–5 are obvious over Flohr2:
Claims 1–5 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S. Patent Application Publication No. 2006/0122168 to Flohr et al. (hereinafter, “Flohr2”).
Flohr2 teaches γ-secretase inhibitors directed to the treatment of Alzheimer’s disease (Abstract) having a formula
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where the variable groups are as defined. For example, X can be —CR4R4′—O— (alkoxylated carbon), R1 and R2 can be hydrogen, alkyl, or various other groups; and R3 and R4 can be alkyl or various other groups.
The compound genus of Flohr2 thus overlaps with the compound genus of instant claim 1. Flohr2 further teaches, inter alia, the following three working examples:
N-((6R,7S)-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2-methoxy-N′-(2,2,3,3,3-pentafluoro-propyl)malonamide (Example 41, paragraph [0333]); and
2-methoxy-N-((6R,7S)-6-methyl-8-oxo-3-trifluoromethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide (Example 62, paragraph [0409]).
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Each of these is a species of instant formula (I), but they are also the fifth and sixth expressly disclaimed species of instant claim 1, and for that reason are not anticipated by claim 1. However, obvious variants of these compounds, according to the teachings of Flohr2, would be compounds of instant claim 1, as well. For example, as noted above, Flohr2 teaches that R1 and R2 can each be hydrogen or alkyl, and teaches working examples with different variations at these positions, such as 2-methyl-N—((S)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide (claim 6).
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While this is not a compound of instant formula I, because it has a methyl rather than an alkoxy substituent on the central malonamide carbon, this exemplifies suitable alternatives within the structural framework of γ-secretase inhibitors of Flohr2. It would have been obvious to modify the compounds such as Example 41 and Example 62 of Flohr2, by providing them with suitable alternative substituent patterns such as omitting the 2-fluoro or 3-trifluoromethyl substituent, or including an N-methyl substituent, on the 5-oxa-9-aza-benzocyclohepten-7-yl ring system, as these are expressly taught variations within Flohr2. One would have had a reasonable expectation of success in producing an effective γ-secretase inhibitor because Flohr2 teaches these as suitable variations for such effective inhibitors.
Such obvious variants of the expressly disclosed compounds of Flohr2 would be species of instant claims 1-5, and claims 1-5 are therefore obvious over Flohr2.
Claims 1–5 are obvious over Flohr3:
Claims 1–5 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S. Patent Application Publication No. 2007/0225273 to Flohr et al. (hereinafter, “Flohr3”).
Flohr3 teaches γ-secretase inhibitors directed to the treatment of Alzheimer’s disease (Abstract) having a formula
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where the variable groups are as defined (paragraph [0037]). For example, A1 can be -CHR- or −C(O)−; A2 is −C(O)−; and R, R1, R2, and R4 can be hydrogen, alkyl, or various other groups.
The compound genus of Flohr3 thus overlaps with the compound genus of instant claim 1. Flohr3 further teaches, inter alia, the following three working examples:
N—[(S)-5-(2-Hydroxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-methoxy-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide (Example 11, paragraph [0157]);
2-ethoxy-N-[(S)-5-(2-hydroxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,3,3,3-pentafluoro-propyl)malonamide (Example 17, paragraph [0181]) – including epimers in Example 18; and
2-Methoxy-N—[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide (Example 68, paragraph [0315]).
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Each of these is a species of instant formula (I), but they are also the first through fourth expressly disclaimed species of instant claim 1, and for that reason are not anticipated by claim 1. However, obvious variants of these compounds, according to the teachings of Flohr3, would be compounds of instant claim 1, as well. For example, as noted above, Flohr3 teaches that R1 can be hydrogen (as in Examples 11 and 17) or alkyl (as in Example 68). It thus would have been obvious to exchange these demonstrably suitable substituents, for example by replacing the R1 hydrogen of Example 11 with the R1 methyl group of Example 68 (or vice versa). One would have had a reasonable expectation of success in producing an effective [Symbol font/0x67]-secretase inhibitor by exchanging suitable substituents in this manner.
Such obvious variants of the expressly disclosed compounds of Flohr3 would be species of instant claims 1-5, and claims 1-5 are therefore obvious over Flohr3.
Allowable Subject Matter
Claims 13-14 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
Prosecution Insights