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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/26/2025 has been entered.
Claim Status
Claims 1-2 are pending and under examination.
Priority
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See filing receipt dated 4/18/2024. Claims 1-2 can only claim priority to the filing date of PCT/US2018/042503 (7/17/2018) as the claimed amorphous solids are not disclosed in 62/653736 or 62/533944.
Claim Rejections - 35 USC § 103
See p. 3-8 of the OA dated 6/26/2025 for the rejection of record. The rejection has been modified to include additional supporting reference to rebut the Applicant’s declaration filed on 10/28/2025.
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-x is/are rejected under 35 U.S.C. 103 as being unpatentable over xxx.
Claim(s) 1-2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Knorr (US 5767309, published on 6/16/1998, of record) in view of Nakanishi (US2014/0309453, published on 10/16/2024, of record), Willms (US 6359162, published on 3/19/2002, of record), Vranic (“Amorphous Pharmaceutical Solids” BOSNIAN JOURNAL OF BASIC MEDICAL SCIENCES 2004; 4 (3): 35-39 35, of record), and Stagnari (“A Review of the Factors Influencing the Absorption and Efficacy of Lipophilic and Highly Water-Soluble Post-Emergence Herbicides, The European Journal of Plant Science and Biotechnology, 2007, p. 22).
Applicant Claims
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Determining the Scope and Content of the Prior Art (MPEP §2141.01)
Knorr teaches processes for preparing (L)- or (D)-homoalanine-4-yl-(methyl)phosphinic acid (glufosinate) and salts thereof by racemate resolution. See abstract and claims. The compound of formula (L-Ia) of Knorr is glufosinate and the compound of formula (L-Ib) of Knorr is ammonium glufosinate, which is an herbicide. See col. 1, lines 1-20. Knorr teaches that the ammonium salt can be formed by dissolving glufosinate free acid in a suitable solvent and passing in ammonium or a solution of ammonia in a solvent. More of the crystallization solvent is then added to precipitate the ammonium glufosinate salt from solution. See col. 3, lines 34-50.
Knorr also teaches that (L) or (D) ammonium glufosinate can be prepared from the D/L ammonium salt by two related selective diastereomeric crystallization methods. Both methods include reacting the racemic ammonium glufosinate with a chiral base in a solvent mixture of water and an organic solvent which solubilizes the racemic ammonium glufosinate salt to produce a mixture of diastereomeric salts. One of the two diastereomeric chiral salts falls out of solution and is separated by filtration, while the other remains in the mother liquor. The salt in the mother liquor can be racemized and returned to the previous step, while the desired diastereomeric salt which has precipitated from the solution and collected by filtration is reacted with ammonia in the presence of an organic solvent to produce the D or L enantiopure ammonium salt, which precipitates out of solution and collected. See col. 5, lines 45-col. 7, line 55. Also see Table I in col. 7.
Knorr teaches that the temperature of the final crystallization stage to obtain the enantiopure D or L ammonium glufosinate salt is preferably carried out at a temperature in the range of 0 to 60C. See col. 6, lines 10-17 and col. 7, lines 17-18. Knorr teaches that suitable solvents for the crystallization include those recited in col. 3, lines 4-18. Also see col. 7, lines 48-54. In the examples, methanol is the preferred solvent for the process steps and the crystallization. See col. 7-9.
Vranic is a general teaching regarding amorphous (non-crystalline) pharmaceutical solids. See whole document. Vranic teaches that amorphous pharmaceutical solids are known in the art and that their properties can be exploited to improve the performance of pharmaceutical dosage forms, including bioavailability and dissolution rate. See abstract, conclusion, and “properties of amorphous solids” section on p. 36. Vranic further teaches that many different crystallization methods can be employed to obtained amorphous solids. Vranic teaches that amorphous solids can also be formed by degradation of crystalline precursors. See “preparation of amorphous solids” section on p. 35-36. Vranic also teaches that amorphous solids are characterized by a glass transition temperature (Tg) rather than a melting point. See “changes” section on p. 37.
Nakanishi discloses a method for producing crystalline glufosinate P free acid. See abstract and claims. Nakanishi teaches that non-crystalline (amorphous) 4-(hydroxymethylphosphinyl)-2-oxo-butyric acid (glufosinate free acid) is known in the art as an active ingredient of an herbicide and that it possesses high hygroscopicity. See [0003-0004] and example 22 in [0090-0094]. Nakanishi further teaches that ammonium glufosinate is a well-known intermediate in the synthesis of the free acid. See [0007-0011]. Nakanishi teaches that the Glufosinate P free acid and its crystal can be in salt form such as sodium, potassium, ammonium, etc…. See [0037].
Willms teaches a method for producing glufosinates and intermediates for the same. See abstract and claims. Willms teaches that ammonium glufosinate is commercially available and is used as a foliar herbicide. See col. 1, lines 9-20. Willms teaches examples of obtaining purified ammonium glufosinate by crystallization from methanol. See examples 3 and 4 in col. 10-11.
Stagnari teaches a review of the factors influencing the absorption and efficacy of lipophilic and highly water-soluble post-emergence herbicides. Stagnari teaches:
“It is well known that post-emergence herbicide uptake into plant foliage and efficacy varies with plant and chemicals, and can be greatly influenced by adjuvants and environmental conditions. The penetration of herbicides into plant leaves is related to the physicochemical properties of the active ingredients, especially molecular size and lipophilicity. For a specific herbicide, uptake varies greatly with plant species and there is no simple method at the moment to quickly evaluate the leaf surface permeability of a plant. Furthermore, current evidence suggests that highly-water soluble, ionic herbicides may be more sensitive to some environmental conditions (low humidity and
rapid drop drying) than lipophilic herbicides.” See abstract.
On p. 29, Stagnari addresses the factor of humidity: “The effect of humidity on the efficacy of herbicides is an area that has received little systematic scientific study under field and controlled environment growth room conditions. This lack of research most relates to difficulty in designing experiments and controlled environment growth chambers where water content of air is held constant while eliminating the effect of temperature on herbicide uptake. Temperature and humidity have both a profound effect on herbicide uptake, and although humidity and temperature interactions
can vary from species to species, many researchers found that humidity has a greater influence on herbicide efficacy than temperature…”. With regard to glufosinate ammonium: “Anderson et al. (1993) following the evaluation of glufosinate ammonium efficacy on barley (Hordeum vulgare) and green foxtail (Setaria faberi) at various combinations of high and low humidity and temperatures regimes, reported that humidity had a greater impact on efficacy than temperature.” See “Humidity” section on p. 29, first paragraph.
Stagnari further teaches in the “Humidity” section on p. 29, that: “Several investigators have suggested that uptake and efficacy are affected more by high humidity after spraying than before (Cook et al. 1977; Lym 1992; Ramsey et al.
2002). According to these researchers, one of the chief benefits of high humidity was the prevention of herbicide crystallization, which depletes the concentration of the
active ingredient in the solution, thereby decreasing penetration. These findings agree with those of others who found that herbicide deposits with good uptake and efficacy were associated with amorphous or gel-like deposits with no crystals (Hess et al. 1981; MacIsaac et al. 1991).”.
Stagnari also teaches that “It is often assumed that the foliar uptake of an herbicide from a crystalline deposit will be less than that from an amorphous one. There are many papers in the open literature (Hess et al. 1986; Hess and Falk 1990) that indicate that production of a crystalline deposit of an herbicide is detrimental to subsequent penetration... However, whilst surfactant addition will undoubtedly ensure that there is an intimate contact between the agrochemical, in a non-crystalline state, and the cuticle surface, foliar uptake from an amorphous deposit may be little different from that of the crystalline form, may be less or enhanced.” See p. 30, second column, second full paragraph.
Stagnari also teaches that : “Differences in cuticle structure might explain some variation in cuticle permeability… Diffusion across the transport-limiting barrier is thought to occur only in the amorphous wax phase which provides a tortuous diffusion path across the wax while crystalline phase can be regarded as an excluded volume with respect to diffusion”. See p. 28, paragraph bridging col. 1-2.
Stagnari also teaches that ammonium salts are known herbicide adjuvants and that ammonium glufosinate has improved efficacy as compared to the free acid. See penultimate paragraph in second col. o fp. 31.
Thus, Stagnari teaches that amorphous herbicides, including ammonium glufosinate, may have improved properties as compared to crystalline herbicides with respect to absorption and efficacy when used as a post-emergence herbicide on formed plant leaves.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.02-03)
Knorr teaches a process which produces solid ammonium glufosinate. Knorr does not explicitly teach that the ammonium glufosinate produced is amorphous/non-crystalline.
Vranic teaches that amorphous solids are known in the art, as are their preparation and uses in pharmaceuticals. Vranic does not explicitly teach amorphous ammonium glufosinate.
Nakanishi explicitly teaches that amorphous glufosinate free acid is known in the art. Nakanishi does not explicitly teach amorphous ammonium glufosinate.
Willms teaches that ammonium glufosinate is commercially available in the art. Willms does not explicitly teach amorphous ammonium glufosinate.
Stagnari teaches that amorphous herbicides, including ammonium glufosinate, may have improved properties as compared to crystalline herbicides with respect to absorption and efficacy when used as a post-emergence herbicide on formed plant leaves.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Knorr, Vranic, Nakanishi, Willms, and Stagnari to arrive at the claimed invention with a reasonable expectation of success before the effective filing date of the instant invention. A person of ordinary skill would have motivated to prepare amorphous solids of glufosinate ammonium, a known herbicide as described in Knorr, Nakanishi, and Willms, because Vranic teaches that amorphous solids are known in the art and that their properties can be exploited to improve the performance of pharmaceutical dosage forms, including bioavailability and dissolution rate. Further, Stagnari teaches that amorphous forms of herbicides have superior absorption and efficacy when used as post-emergence herbicides on formed plants. Therefore, while ammonium glufosinate is not a pharmaceutical, it does have industrial use as an herbicide that may benefit from the properties of an amorphous solid vs. a crystalline solid during application.
Further, Nakanishi teaches that it is known that glufosinate free acid can be obtained as an amorphous solid, which indicates that the ammonium salt thereof can also be obtained as an amorphous solid. Willms teaches that ammonium glufosinate is commercially available and teaches it can be crystallized from methanol. Knorr teaches several examples of solid ammonium glufosinate in the examples and a process for generally obtaining said compound in highly pure form. Vranic teaches that amorphous solids can be formed as degradation products of crystalline solids, among many other traditional methods. Knorr teaches that highly enantiopure D or L ammonium glufosinate can be obtained from the glufosinate free acid or racemic ammonium glufosinate and provides a wide range of solvents and temperatures for crystallizing the final ammonium glufosinate solid. It is noted that the temperature range taught by Knorr of 0-60C overlaps with that described in the specification as filed of 50-60C that was used to prepare the instantly claimed amorphous ammonium glufosinate from a slurry in a solvent. See MPEP 2144.05 and p. 64 of the specification as filed. Additionally, Knorr explicitly teaches that one of the three solvents described in the specification, NMP, is an acceptable crystallization solvent in the method. See col. 3, lines 4-18. The specification as filed further appears to indicate that any of the amorphous ammonium glufosinate forms desired inherently possess the claimed glass transition temperature of claim 2. See section 6 on p. 64.
The Office does not have the resources to check every vendor and/or batch of ammonium glufosinate prepared to see if any were amorphous or if any underwent degradation to form an amorphous product. However, as discussed in the rejection above, the prior art provides both motivation to prepare an amorphous version of ammonium L-glufosinate (Vranic and Stagnari) and known methods to obtain solid forms of ammonium L-glufosinate (Nakanishi, Wilms, Knorr) as well as well-known general methods to produce amorphous solids (Vranic). Therefore, it would have been prima facie obvious to obtain the amorphous forms of ammonium L-glufosinate by optimizing known procedures according to known techniques with a reasonable expectation of success before the effective filing date of the instant invention.
Applicant Arguments on p. 3-6 of the response filed 10/28/2025, including a declaration filed under 37 CFR 1.132, also filed 10/28/2025
The Applicant argues:
“Applicant respectfully disagrees, and asserts that a person of ordinary skill in the art would not have been motivated to make amorphous ammonium glufosinate based on any of Knorr, Vranic, Nakanishi, or Willms (individually or in combination).
As stated by Dr. Viertelhaus: A person of ordinary skill in the art would have been motivated make
amorphous L-glufosinate ammonium based any of Knorr, Vranic, Nakanishi, or Willms (individually or in combination). L-glufosinate ammonium is the active ingredient for a herbicidal formulation. As the active ingredient, it needs to be processed and stored as a free flowing power, which allows dosing in high quantities from a large bag. Because of this, a person of ordinary skill in the art would understand it is highly undesirable to have a hygroscopic material or a brittle material. In the worst case, a hygroscopic material goes deliquescent. If the material agglomerates, it may bake and become brittle. Thus, neither hygroscopicity nor brittleness is an advantage to a herbicidal active ingredient. Viertelhaus Declaration at paragraph 7. In view thereof, Vranic provides no motivation to a person of ordinary skill in the art to prepare amorphous L-glufosinate ammonium.
The Office Action states that "[r]egarding Nakanishi, in [0005] Nakanishi is referring to the free acid, which is not claimed" and "[t]hus, Nakanishi is not explicitly teaching away from the claimed invention." Office Action at p. 10.
However, a person of skill in the art would understand that Nakanishi recognizes the undesireability of amorphous, highly hygroscopic herbicides. As stated by Dr. Viertelhaus:
I understand that Nakanishi discloses that a certain prior art method
for producing glufosinate P and states the method had "an industrial problem
in that since the obtained powder is a non-crystalline form, its
hygroscopicity is very high." Nakanishi at paragraph [0005] (emphasis
added).
A person of ordinary skill in the art would understand that such hygroscopicity is highly undesirable for a herbicidal active ingredient. In addition to potentially going deliquescent or agglomerating, such
hygroscopicity provides an undefined solid material which, for an active ingredient that needs to be formulated, causes extra analysis to be conducted before formulation. That is, at high humidity higher water is seen in such hygroscopic material and will have to be analyzed to determine the amount of
active ingredient present before weighing for formulation.
Viertelhaus Declaration at paragraph 8. In view thereof, Nakanishi provides no motivation to a person of ordinary skill in the art to prepare amorphous L-glufosinate ammonium.
The Office Action states that "it is also prima facie obvious that amorphous L- glufosinate ammonium will form over time, if it does not inherently exist, in the commercially available samples." Office Action at p. 11. However, as explained by Dr. Viertelhaus, amorphous L-glufosinate ammonium would not inherently form from a crystalline precursor:
I disagree with this statement. As described by Vranic et al.:"thus the major stability concern for amorphous materials is with their tendency to revert to the crystalline state". Vranic et al. at p. 37. This means that amorphous material can convert by itself into crystalline. This is supported by Vranic et
al., which states that one "aim of stabilization of amorphous solids" is for "the prevention of rystallization". Id. Amorphous material is of higher energy than crystalline material. Thermodynamics never allows a system to go up in energy without being forced. Therefore, amorphous material cannot be
formed from crystalline material without force, e.g. intermediate systems like
solution or melt. ... Viertelhaus Declaration at paragraph 11.
With respect to Knorr, the Office Action indicates that "the conditions of Knorr are substantially similar to those claimed" and that "if the products of the examples of Knorr are not inherently amorphous, then amorphous forms thereof can predictably be obtained from Knorr." Office Action and page1 and page 8, respectively.
Applicant respectfully disagrees. As explained by Dr. Viertelhaus, the reaction conditions of Knorr et al. do not lead to amorphous L-glufosinate ammonium:
The reaction conditions of Knorr et al. do not lead to amorphous L- glufosinate ammonium. As described in the Examples of Knorr et al., the
reactions produced crystals that were filtered off at room temperature
(amorphous material cannot be filtered). As described in the application as
filed, sustained high temperatures are needed to produce amorphous material:
X-ray amorphous material was collected from slurries in
solvents such as N-methyl-2-pyrrolidone (NMP),
tetrahydrofuran (THF), and 2,2,2-trifluoroethanol (TFE), which were maintained at temperatures ranging from 50 OC to 60 OC
for extended periods (e.g., 12 days). 1 H NMR analysis of
amorphous L-glufosinate ammonium was consistent with the structure and showed the presence of minor unknown peaks.
Thermal analysis of the material revealed an apparent glass
transition, Tg, at ~55 'C.
Application as filed, page 58, line 34 - page 59, line 4 (emphasis added).
Knorr et al., however, does not disclose maintenance of any slurry for such an extended period and temperature.
Viertelhaus Declaration at paragraph 11.
In view of the above, Applicant asserts that the claimed invention is not obvious over the cited art, and respectfully requests that the rejection be withdrawn.”
With respect to the Applicant’s arguments that Vranic does not provide sufficient motivation to obtain ammonium L-glufosinate because it is directed to pharmaceuticals and not herbicides, the arguments have been fully considered but are not persuasive. As further supported by Stagnari, amorphous water-soluble herbicides are often more efficacious and can be absorbed more readily than crystalline counterparts when said herbicides are employed as post-emergence herbicides. See full discussion of Stagnari in the preceding rejection. Therefore, though the Applicant and Declaration argue that a person of ordinary skill would not have been motivated to make amorphous ammonium glufosinate because it allegedly is harder to handle and store, Stagnari teaches that amorphous forms of herbicides are expected to possess improved absorption and efficacy when they are contacted with the plant. Therefore, Stagnari further supports the teachings of Vranic in that modifying the crystallinity and physical form of active ingredients can alter the properties of said ingredients, wherein Stagnari further explicitly teaches expected benefits of amorphous forms of herbicides during application.
Regarding Applicant’s statements in the declaration clarifying the starting materials of Example 16 as not being commercially derived, these arguments are persuasive. However, it is noted that this was not relied upon for the prior art rejection and was only mentioned by the Examiner in the response to the Applicant’s arguments in the previous OAs.
Regarding the Applicant’s arguments that Vranic allegedly teaches that amorphous material cannot be formed from non-amorphous material has been fully considered but is not persuasive. The small portion of Vranic cited by the Applicant indicates that amorphous solids can revert back to the crystalline state. However, Vranic also teaches that many different crystallization methods can be employed to obtained amorphous solids and that amorphous solids can be formed by degradation of crystalline precursors. See “preparation of amorphous solids” section on p. 35-36. Further, in the first paragraph of said section, Vranic recites : “The preparation of amorphous solids, for thermodynamic and kinetic reasons, is easy for some materials (good glass formers), but difficult for others (poor glass formers).”. Therefore, the Applicant’s broad arguments about thermodynamics as applied to all crystalline systems is not persuasive. It is noted that the statement that “amorphous material cannot be formed from crystalline material without force” is not taught by Vranic and is not supported by any objective evidence in the declaration or disclosure as filed.
However, the Applicant’s arguments regarding the lack of inherency of the amorphous form of ammonium L-glufosinate necessarily forming over time are persuasive. The Office maintains that the process can predictably happen based on the teachings of Vranic, but not that it necessarily does.
Regarding the Applicant’s arguments that the conditions of Knorr do not lead to amorphous L-glufosinate ammonium, the Applicant’s arguments have been fully considered but are not persuasive. Though Knorr does not inherently teach an amorphous solid because there are differences between the inventive crystallization process and that in Knorr as highlighted by the Applicant, Knorr does teach an overlapping temperature range and the use of similar solvents to those of the inventive examples, which are known to produce amorphous ammonium L-glufosinate. Vranic and Stagnari provide motivation to specifically attempt to prepare amorphous ammonium L-glufosinate. Further, as taught by Vranic, amorphous solids can be prepared in a variety of different ways, including the degradation of other crystalline forms. Therefore, it would be reasonable to expect that optimizing the conditions and/or crystals of Knorr according to the techniques of Vranic would provide an amorphous version of ammonium L-glufosinate.
For these reasons, the claims remain rejected.
Conclusion
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/AMY C BONAPARTE/Primary Examiner, Art Unit 1692