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 .
DETAILED ACTION
Claims 1, 4, 9, 12-15, 17, 20, and 25-27 of A. Muthusamy et al., US 17/798,393 (Jan. 22, 2021) are pending and under examination. Claims 4 and 12 are rejected. Claims 1, 9, 13-15, 17, 20, and 25-27 are in condition for allowance.
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 16, 2026 has been entered.
Claim Interpretation
Examination requires claim terms first be construed in terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim. See, MPEP § 2111. Under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. See MPEP § 2111.01.
Here, claim interpretation supplements that of the previous Office action to emphasize the meaning of the two claimed crystalline forms of avasopasem manganese (GC4419) (i.e., Form AM1 and Form AM4), per claims 1 and 9.
Avasopasem Manganese (GC4419)
The claims are directed to two crystalline forms of avasopasem manganese (GC4419) (i.e., Form AM1 and Form AM4) characterized by X-ray powder diffraction pattern (XRPD). Avasopasem manganese (GC4419) (possessing four chiral carbons) is a single enantiomer, has the following structure:
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Specification at page 1, [0002] (where the dotted lines, arrows in the specification depiction, represent coordinate covalent bonds).
Interpretation of Forms AM1 and AM4 as Recited in Claims 1 and 9
Base claims 1 and 9 recite as follows:
1. A crystalline Form AM1 of Avasopasem manganese, characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 7.8, 8.2, 11.2, 14.1 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta; or combinations of these data.
9. A crystalline Form AM4 of Avasopasem manganese, characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 7.9, 14.3, 15.8, 25.4 and 28.0 degrees 2-theta ± 0.2 degrees 2-theta; or combinations of these data.
The specification discloses the XRPD spectra of Form AM1 and Form AM4 in FIGS. 1 and 4 respectively. As well known in the art, the set of lines, their location, and relative intensity, obtained for an XRD powder pattern of a crystalline phase, is characteristic for that phase and represents a kind of fingerprint. J. Blachére et al., X-Ray Diffraction Methods for the Characterization of Solid Pharmaceutical Materials, In Preformulation in Solid Dosage Form Development. Pages 229-252 (2008) (see lines bridging pages 239-240).
Claims 1 and 9 are interpreted, under the plain claim language of:
1. A crystalline Form AM1 . . .
9. A crystalline Form AM4 . . . .
to require the presence/existence of the single and specific crystalline form recited (i.e., either crystalline form AM1 or crystalline Form AM4) displaying characteristic x-ray diffractogram substantially in accordance with specification FIGS. 1 and 4, respectively. That is, claims 1 and 9 require the single crystal form recited (either AM1 or AM4) represented by the set of lines, their location, and relative intensity, per the XRD powder patterns of Fig. 1 and Fig. 4 respectively. In other words, claims 1 and 9 are not directed to a genus of crystal forms; but rather to the single crystal form recited. Specification Figs. 1 and 4 are the unique XRPD fingerprints that differentiate claimed Forms AM1 and AM4 from all other crystalline forms of avasopasem manganese (such as, different polymorphs, amorphous forms, solvates, hydrates, etc.).
Withdrawal Claim Rejections - 35 USC § 112(d)
Upon reconsideration, rejection of claims 13, 14 and 25 under 35 U.S.C. 112(d) is withdrawn. As discussed above, claims 1 and 9 require the single avasopasem manganese crystal form recited (either AM1 or AM4) represented by the set of lines, their location, and relative intensity, per the XRD powder patterns of Fig. 1 and Fig. 4 respectively. Claims 13 and 14 add language that Form AM1, of base claim 1, may contain no more than 20% of specified other forms, which is a further limitation and therefore meets the requirements of § 112(d). Claim 25 has a similar recitation with respect to AM4 and meets the requirements of § 112(d) for the same reasons. It is noted that “the requirements of 35 U.S.C. 112(d) are related to matters of form”. MPEP § 608.01(n)(III). And in some case, dependent limitations of questionable significance can still meet the formal requirements of 112(d). MPEP § 2103(I)(C).
Withdrawal Claim Rejections - 35 USC § 102 (AIA )
Rejection of the instant claims, directed to crystalline forms AM1 or AM4 of avasopasem manganese, under 35 U.S.C. 102(a)(1)/(2) over by J. Keene et al., WO 2018/152353 (2018) (“Keene”) is withdrawn in view of the Declaration of Amit Singh under 37 C.F.R. 1.132 (June 16, 2026) (the “Singh Declaration”).
Keene teaches that GC4419 (avasopasem manganese):
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administered by intravenous (iv) infusion has been shown to reduce oral mucositis in head-and-neck cancer patients undergoing chemoradiation therapy. Keene at page 2, [0004]. Keene is directed to oral dosage forms of Formula (I) (including GC4419). Keene at page 23, [0075]; Id. at page 53, [00166].
Keene teaches that:
[0029] FIG. 12 is an X-ray crystal structure of GC4419 obtained by the methodology reported in Riley et al., Advances in Inorganic Chemistry, Vol. 59, pp.233-263 (2007).
Keene at page 14, [0029].1 Keene’s disclosure is based on a single crystal x-ray analysis. Keene at page 4, lines 1-2.
Keene’s above cited reference, D. Riley et al., 59 Advances in Inorganic Chemistry, 233-263 (2007) (“Riley”), teaches that crystalline M40401-(PF6)2:
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was prepared as follows:
A small amount (50 mg) of complex was added to 1–2mL of boiling water. To this was then added ethanol dropwise until a clear solution resulted and the solution was then filtered through a plug of glass wool and allowed to sit undisturbed. Over the course of several days, the solution yielded crystals suitable for X-ray diffraction and were collected by filtration.
Riley at page 261, last five lines (emphasis added). Thus, Keene effectively teaches that crystalline avasopasem manganese (GC4419) was obtained by slow crystallization from water after dropwise addition of ethanol, per the method of Riley for M40401-(PF6)2. Keene thus likely teaches the thermodynamically stable hydrated polymorphic form of avasopasem manganese (GC4419). That is, if the compound exhibits multiple crystal forms, then the thermodynamically more stable polymorphs will typically be created in the slow crystallizations. Adeyeye at page 42.2
Here, the claims are directed to Forms AM1 or AM4. The issue is whether Keene’s crystalline GC4419 (avasopasem manganese), crystallized according to the method of Riley (from boiling water by dropwise addition of ethanol) is the same crystalline form as either of the claimed Forms AM1 or AM4. Applicant submits the Declaration of Amit Singh under 37 C.F.R. 1.132 (June 16, 2026) (the “Singh Declaration”). The Singh Declaration avers that experiments were performed, designed to replicate, as closely as practicable, the crystallization methodology described in Keene and Riley and characterized the resulting material and the results did not show production of crystalline Form AM1 or crystalline Form AM4. Singh Declaration at ¶ 7. The Singh Declaration avers that the XRPD patterns of the samples prepared according to Keene/Riley do not correspond to instantly claimed crystalline Form AM1 or crystalline Form AM4 of avasopasem manganese. Singh Declaration at ¶ 12.
The evidence presented in the Singh Declaration sufficiently establishes that claimed Forms AM1 and AM4 are different crystalline forms than prior art forms of avasopasem manganese than disclosed by Keene. Accordingly, the § 102 rejection is withdrawn.
Withdrawal Claim Rejections - 35 USC § 103 (AIA )
Rejection of claims 15, 17, 20, and 25-27, directed to pharmaceutical compositions and use of AM1 or AM4 of avasopasem manganese in treatment of oral mucositis, under AIA 35 U.S.C. 103 as being unpatentable over J. Keene et al., WO 2018/152353 (2018) (“Keene”) in view of H.G. Brittain, in Polymorphism In Pharmaceutical Solids (H.G. Brittain ed., 2nd ed., 2009) (“Brittain”) is withdrawn for the following reasons. The obviousness rationale of the previous Office action is that one of ordinary skill is motivated to employ the crystalline avasopasem manganese (GC4419) depicted in Keene Fig. 12, prepared by slow crystallization from water after dropwise addition of ethanol, per the method of Riley, in a pharmaceutical composition for the treatment of oral mucositis in head-and-neck cancer patients undergoing chemoradiation therapy. However, as discussed in detail above Keene does not teach either of Forms AM1 or AM4 of avasopasem manganese. As such, the § 103 rejection is withdrawn because the reference combination does not teach each and every claim limitation.
Maintained Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
A “claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers”. 35 U.S.C. 112(d). However, to be in proper dependent form, the dependent claim must “then specify a further limitation of the subject matter claimed”. 35 U.S.C. 112(d); MPEP § 608.01(n)(III).
Dependent claims 4 and 12 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to incorporate by reference all the limitations of the claim to which the respectively refer or failing to further limit the subject matter of the respective claims upon which they depend. MPEP § 608.01(n)(III). The issue is the claim 4 and 12 recitations of hydrate do not further limit the claims.
Hydrated Forms Have Different Crystal Structure than the Corresponding Anhydrate/Dehydrates
The issue is the claim 4 and 12 recitations of hydrate do not further limit the claims. Before addressing the merits of the rejection, a discussion of hydrate crystal structure versus that of the anhydrate is helpful.
As well known in the art, the set of lines, their location, and relative intensity, obtained for an XRD powder pattern of a crystalline phase, is characteristic for that phase and represents a kind of fingerprint. J. Blachére et al., X-Ray Diffraction Methods for the Characterization of Solid Pharmaceutical Materials, In Preformulation in Solid Dosage Form Development. Pages 229-252 (2008) (see lines bridging pages 239-240).
Hydrates have a different crystal structure than the corresponding anhydrates (aka dehydrates) and therefore exhibit a different XRPD pattern. H. Liu et al., 96 Journal of Pharmaceutical Sciences, 927-934 (2007), (see page 927, col. 2 “[t]herefore, the hydrated pharmaceutical materials have different crystalline forms from those of the anhydrates”). As such, the XRPD of the hydrate will be different than the corresponding anhydrate.
Various technologies have been used to characterize anhydrous and hydrated pharmaceutical materials. However, each one has its own limitations. X-ray powder diffractometry (XRPD) is the most commonly used method based upon distinguishing different crystalline structures
Liu at pages 927-928 (emphasis added); see also Liu at page 930, col. 2 (referencing Fig. 3b showing the XRPD differences between hydrated and anhydrous caffein); Liu at pages 930-931 (referencing Figs. 4b and 5b, respectively showing the XRPD differences between hydrated and anhydrous theophylline and hydrated and anhydrous D-glucose). “[S]pecifically, in terms of hydrate investigation, PXRD helps to differentiate between the hydrated and dehydrated form”. E. Jurczak et al., 12 Pharmaceutics, 1-25 (2020); see also, K. Fujii et a., 12 Crystal Growth & Design, 6165-6172 (2012) (see page 6171 “[i]n this work, crystal structures of dihydrate, monohydrate, and anhydrous phases of lisinopril were successfully determined from PXRD data and the mechanistic aspects of the two-step dehydration of the dihydrate phase of lisinopril were clearly established from these structures”).
The § 112(d) Rejection Rationale
Dependent claims 4 and 12 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to incorporate by reference all the limitations of the claim to which the respectively refer or failing to further limit the subject matter of the respective claims upon which they depend. MPEP § 608.01(n)(III). Claims 4 and 12 recite as follows:
4. The crystalline Form AM1 of Avasopasem manganese according to claim 1 which is a hydrate.
12. The crystalline Form AM4 of Avasopasem manganese according to claim 9 which is a hydrate.
With respect to whether AM1 and AM4 are hydrates or not, the specification is unclear:
[0042] Crystalline Form AM1 of Avasopasem manganese may be a hydrate; more preferably monohydrate. Preferred percentage range for water in the hydrate is 3-5.5%. Alternatively, crystalline form AM1 is a hydrated form comprising about 3 wt% to about 5.5 wt% water, or about 3 wt% to about 5 wt% water. In any embodiment, Form AM1 may comprise about 3.2 wt% to about 4.8 wt% water, and optionally about 3.3wt% to about 3.8 wt% water.
[0072] Crystalline Form AM4 of Avasopasem manganese may be a hydrate; more preferably dihydrate. Preferred percentage range for water is 5 wt% to 9 wt%. In any embodiment Form AM4 may be a hydrate comprising about 5.8 wt% to about 8.5 wt% water, or about 6 wt% to about 7.5 w1% water. In any embodiment, Form AM4 may comprise about 6.5 wt% to about 7 wt% water.
Specification at [0042], [0072].
In any case, claims 4 and 12 fail to further limit their respective base claims because the base claims 1 and 9 are limited (per Claim Interpretation above) to a single crystalline form, and the further dependent-claim recitation of hydrate either: (1) does not further limit the base claim, because it is already the hydrate; or (2) does not incorporate all the limitations of the base claim because the dependently claimed hydrate is a different crystalline form than that of the base claim. Which one of these rationales applies is not clear from the specification.
The main case on point is Pfizer, Inc. v. Ranbaxy Labs. Ltd., 457 F.3d 1284 (Fed. Cir. 2006). In Pfizer, Inc. v. Ranbaxy Labs. Ltd., the claims at issue were:
1. [R-(R*,R*)]-2-(4-fluorophenyl)-β,σ-dihydroxy-5-(1-methylethyl)-3-pheny-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid[fn4] or (2Rtrans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,]4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran -2-yl)ethyl]-1H-pyrrole-3-carboxamide;[fn5] or pharmaceutically acceptable salts thereof.
2. A compound of claim 1 which is [R(R*R*)]-2-(4-fluorophenyl)-(β-σ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.
6. The hemicalcium salt of the compound of claim 2.
In Pfizer, claim 6 was the focus of the § 112(d) analysis. Pfizer, Inc. v. Ranbaxy Labs. Ltd. at 1291. The court first noted that claim 2 only recites atorvastatin acid and does not include the pharmaceutical acceptable salts of atorvastatin acid. Id. The court held that claim 6 was invalid under § 112(d) because it did not "specify a further limitation of the subject matter" of claim 2. Id. at 1292 (“Ranbaxy correctly argues that claim 6 fails to "specify a further limitation of the subject matter" of the claim to which it refers because it is completely outside the scope of claim 2”). The court held claim 6 does not narrow the scope of claim 2; instead, the two claims deal with non-overlapping subject matter.
Here, if base claims 1 and 9 are not already the hydrates, then as in Pfizer, Inc. v. Ranbaxy Labs. Ltd., dependent claims 4 and 12 deal with subject matter non-overlapping with their respective base claims. On the other hand, if base claims 1 and 9 are already hydrates, then claims 4 and 12 do not further limit their respective base claims.
It is noted that “the requirements of 35 U.S.C. 112(d) are related to matters of form”. MPEP § 608.01(n)(III). And in some case, dependent limitations of questionable significance can still meet the formal requirements of 112(d). MPEP § 2103(I)(C). However, the issue here is more than a matter of form, but rather is a substantive aspect of interpreting claims 4 and 12.
Applicant’s Argument
Applicant argues that The XRPD patterns of Figures 1 and 4 characterize the crystal structures of Forms AM1 and AM4 respectively, but do not and cannot specify the water content or hydration state of the bulk sample and the Office's position that the XRPD pattern confirms that a hydrate is a distinct solid-state form not necessarily encompassed by the base XRPD characterization. Reply at page 5. Applicant argues that a sample of Form AM1 or Form AM4 that is not a hydrate and a sample that is a hydrate may each produce an XRPD pattern corresponding to the respective form under certain conditions, yet only the latter falls within the scope of claims 4 and 12 respectively and the hydration state limitation thus meaningfully narrows the respective independent claim in a manner that is analytically distinct from the XRPD fingerprint. Reply at pages 5-6.
Examiner Response
This argument is not persuasive for the following reasons. First, as discussed above, the art teaches that a hydrate and the corresponding anhydrate will have distinct XRPD patterns. As discussed above in Claim Interpretation, base claims 1 and 9 require the single crystal form recited (either AM1 or AM4) represented by the set of lines, their location, and relative intensity, per the XRD powder patterns of Fig. 1 and Fig. 4 respectively. In other words, claims 1 and 9 are not directed to a genus of crystal forms (for example, a genus encompassing both hydrates and anhydrates); but rather to the single crystal form represented by the corresponding XRPD spectrum, which is either the hydrate or not the hydrate (it is unclear from the specification which applies). Specification Figs. 1 and 4 are the unique XRPD fingerprints that differentiate claimed Forms AM1 and AM4 from all other crystalline forms of avasopasem manganese (such as, different polymorphs, amorphous forms, solvates, hydrates, anhydrates, etc.).
The term “hydrate” has a specific meaning in the art in that water is incorporated in the crystal lattice. E. Jurczak et al., 12 Pharmaceutics, 1-25 (2020) (see page 1); see also, R. Khankari et al., 248 Thermochimica Acta, 61-79 (1995) (see page 62: “In hydrates water occupies definite positions in the crystal lattice, usually by forming hydrogen bond(s) and/or coordinate covalent bond(s) with the anhydrate drug molecules”). Similarly, Martino teaches that:
Water can be adsorbed onto the solid surface and/or may be absorbed into the bulk solid structure. Usually, this water can be retained onto or into the solid, but some species, such as the hydrates, can incorporate water molecules, usually stoichiometrically, into their crystal lattice. Water then occupies definite positions in the crystal lattice, usually forming hydrogen bond(s) and/or coordinate covalent bond(s) with the anhydrate drug molecules.
P. Martino et al., 14 European Journal of Pharmaceutical Sciences, 293-300 (2001) (page 291, emphasis added, citations omitted).
The Examiner accepts, as argued by Applicant, that crystal forms may have different levels of hydration, and the hydration level does not necessarily affect the underlying crystal structure; for example, a crystalline form may be wetted or adsorb water, but is not necessarily a “hydrate” with water incorporated into the crystal lattice.
However, claims 4 and 12 are directed to “hydrates” (where water is incorporated into the crystal lattice) not to wetter forms of AM1 or AM4. Here, if base claims 1 and 9 are not already the hydrates (where water is incorporated into the crystal lattice), then dependent claims 4 and 12 deal with subject matter non-overlapping with their respective base claims. On the other hand, if base claims 1 and 9 are already hydrates, then claims 4 and 12 do not further limit their respective base claims.
Subject Matter Free of the Art of Record
Claims 1, 4, 9, 12-15, 17, 20, and 25-27 are free of the art of record. Per base claims 1 and 9, the claims are directed to two crystalline forms of avasopasem manganese (GC4419) (i.e., Form AM1 and Form AM4) as AM1 and AM 4 are interpreted above as a single/unique crystalline form.
It is well known in the art that compounds can exhibit different crystalline forms. E. Jurczak et al., 12 Pharmaceutics, 1-25 (2020) (see page 4, lines 1-2 “[s]tatistically, approximately one-third of pharmaceutical solids exist in at least two forms, differing in the level of hydration”). However, the prior art teaches that the specific crystalline forms of complex small molecule pharmaceuticals that can be obtained is generally unpredictable. See e.g., A.J. Cruz-Cabeza et al., 44 Chemical Society Reviews, 8619-8635 (2015) (see page 8633, col. 1 “[a]lthough we have shown that there may be some possible trends, the truth remains that polymorphism is unpredictable on the basis of molecular structure”). The formation of polymorphic/crystalline forms remains unpredictable as of the instant filing date.
Polymorphism, the ability of a material to crystallize in different solid forms, is highly common and mostly unpredictable based on molecular structure. This poses a challenge, especially in the manufacturing of effective drugs, where active pharmaceutical ingredients (APIs) may crystallize in polymorphic forms that differ greatly in their physical and chemical properties, like solubility and bioavailability. The polymorphism of many APIs is known, and the various structures have been characterized and studied extensively. However, there is still a lack of feasible methods for directed crystallization of the desired forms, as this requires an in-depth understanding of the factors that drive crystallization to different polymorphs.
R. Herboth et al., 9 ACS Omega, 36718-36731 (2024) (at page 36718, col. 1).
The Claims Are Free of the Closest Art of Record
The closest art of record is J. Keene et al., WO 2018/152353 (2018), as discussed in detail above and in the previous Office action. As discussed, Keene teaches a single crystalline form avasopasem manganese:
[0029] FIG. 12 is an X-ray crystal structure of GC4419 obtained by the methodology reported in Riley et al., Advances in Inorganic Chemistry, Vol. 59, pp.233-263 (2007).
Keene at page 14, [0029]. Keene’s Fig. 12 is based on a single crystal x-ray analysis, that cannot be compared to the instant specifications XRPD data. Keene at page 4, lines 1-2. However, as discussed above, the evidence presented in the Declaration of Amit Singh under 37 C.F.R. 1.132 (June 16, 2026) (the “Singh Declaration”) sufficiently establishes that claimed Forms AM1 and AM4 are different crystalline forms than the crystallin form of avasopasem manganese disclosed by Keene.
The claims are not obvious in view of Keene because neither Keene nor secondary art teaches that avasopasem manganese can exist in different crystalline forms let alone suggest, or motivate one of ordinary skill to seek out, the instantly claimed crystalline forms AM1 or AM4.
Conclusion
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 This is an ORTEP drawing, which is an illustration of the molecular structure, used to visualize the positions of atoms and their thermal motion in a crystal structure. See J. Keene et al., US 2013/0079317 (2013), Fig. 2; Id. at page 2, [0022] (disclosing in Fig. 2, the same representation as Keene Fig. 12); Id. at page 37, [0576]; Id. at page 37, [0577] (disclosing synthetic methods).
2 Supporting evidence is also provided by H.G. Brittain, in Polymorphism in Pharmaceutical Solids (H.G. Brittain ed., 2nd ed., 2009) (“Brittain”). Brittain teaches that as a general principle, slow crystallization and transformation processes operated under mild conditions with moderate driving forces are more likely to produce stable crystalline polymorphs, whereas rapid processes employing dynamic and extreme conditions with large driving forces will produce metastable and unstable crystalline forms and amorphous solids. Brittain at page 87 (see also pages 77-78). In summary of this paragraph, under a particular set of crystallization conditions, one polymorphic form is kinetically favored over another; this kinetically more favored form may be the most thermodynamically stable form or a metastable form that could potentially interconvert to the most thermodynamically stable form.
Prosecution Insights