Patent Application 17798393 - SOLID STATE FORMS OF AVASOPASEM MANGANESE AND

Title: SOLID STATE FORMS OF AVASOPASEM MANGANESE AND PROCESS FOR PREPARATION THEREOF

Application Information

Invention Title: SOLID STATE FORMS OF AVASOPASEM MANGANESE AND PROCESS FOR PREPARATION THEREOF
Application Number: 17798393
Submission Date: 2025-05-15T00:00:00.000Z
Effective Filing Date: 2022-08-09T00:00:00.000Z
Filing Date: 2022-08-09T00:00:00.000Z
National Class: 556
National Sub-Class: 045000
Examiner Employee Number: 88182
Art Unit: 1692
Tech Center: 1600

Rejection Summary

102 Rejections: 3
103 Rejections: 1

Cited Patents

The following patents were cited in the rejection:

US 0079317🔗

Office Action Text

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 1-15, 17, 18, and 20-28 of A. Muthusamy et al., US 17/798,393 (Jan. 22, 2021) are pending and under examination and are rejected.

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. It is also appropriate to look to how the claim term is used in the prior art, which includes prior art patents, published applications, trade publications, and dictionaries. MPEP § 2111.01 (III).

Avasopasem Manganese (GC4419)

The claims are directed to three crystalline forms of avasopasem manganese (GC4419) (i.e., Form AM1, Form AM2, 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). Avasopasem manganese (GC4419) is the enantiomer of GC4403 (also known in the art as M40403 or SC-72325). See e.g., C. Weekly et al., 56 Inorganic Chemistry, 6076-6093 (2017) (“Weekly”) (see, Weekly at page 6077, Scheme 1). Weekly teaches that avasopasem manganese (GC4419) has entered phase 2 trials for protection against chemoradiation-therapy-induced oral mucositis (NCT02508389). Weekly at page 6077, col. 1. Weekly cites C. Anderson et al., Phase 1b/2a Trial of Superoxide (SO) Dismutase (SOD) Mimetic GC4419 to Reduce Chemoradiation Therapy−Induced Oral Mucositis (OM) in Patients With Oral Cavity or Oropharyngeal Carcinoma (OCC), 94 Int. J. Radiat. Oncol., Biol., Phys., 869-870 (2016) (“Anderson”).

Specification Working Examples – Preparation of Crystal Forms AM1, AM2, and AM4

The crystallization conditions are relevant as to the crystal form produced. In this regard, the art teaches that bulk materials are generally crystallized in a rapid process where there is a high degree of supersaturation that leads to a metastable crystal form (kinetic control). H.G. Brittain, Preparation and Identification of Polymorphs and Solvatemorphs, in Preformulation in Solid Dosage Form Development 185-228 (M. C. Adeyeye et al., eds., 2008) (“Adeyeye”) (see Adeyeye at page 42). 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.

In view of the specification working examples (as summarized below), the various crystalline forms of avasopasem manganese (AM1, AM2, and AM4) apparently interconvert into one another depending upon the conditions employed.

Specification Preparation of avasopasem manganese (GC4419), Form AM1

The specification working examples teach that avasopasem manganese (GC4419), Form AM1 can be prepared by:

(1) Crystallization of avasopasem manganese from dichloromethane. After, 2 days, the obtained solid was analyzed by XRD- Form AM1. Specification at page 24, Example 1.

(2) Crystallization of Form AM2 from isopropanol. Specification at page 26, Example 10.

(3) Crystallization of Form AM4 from ethanol. Specification at page 26, Example 11;

(4) Crystallization of Form AM2 from water. Specification at page 26, Example 12.

(5) Crystallization of Form AM2 from ethanol by addition of methyl-tertbutyl ether. Specification at page 26, Example 13.

Specification Preparation of avasopasem manganese (GC4419), Form AM2

The specification working examples teach that avasopasem manganese (GC4419), Form AM2 can be prepared by:

(1) Crystallization of avasopasem manganese from tetrahydrofuran/water. After, 2 days, the obtained solid was analyzed by XRD- Form AM2. Specification at page 24, Example 2.

(2) Stirring a suspension of Form AM1 in water at 0-5 deg and filtering the resulting slurry. Specification at page 26, Example 14.

(3) Stirring a suspension/slurry of Form AM1 in water/1,2-demethoxyethane. Specification at page 27, Example 15.

(4) By a relatively fast crystallization of Form AM4 in water/1,2-demethoxyethane over four hours. Specification at page 27, Example 16.

Specification Preparation of avasopasem manganese (GC4419), Form AM4

The specification working examples teach that avasopasem manganese (GC4419), Form AM4 can be prepared by:

(1) By stirring Form AM1 (800 rpm) in 1,2-dimethoxyethane/water at 85 °C, cooling to 70 °C and stirring the slurry (800 rpm) at 70 °C, then cooling the slurry to 25 °C and filtering. Specification at page 24, Example 4.

(2) By heating a suspension of Form AM1 in water to 60 °C and stirring (800 rpm), filtering at 60 °C. Specification at page 25, Example 5.

(3) By exposing avasopasem manganese to 90% relative humidity at 60 °C for three days. Specification at page 27, Example 17.

(4) By maintaining a slurry of Form AM1 in a mixture of isopropyl alcohol/water (90:10) at 60 °C for 1 day and filtering the hot mixture. Specification at page 27, Example 18.

Interpretation of the Crystalline Forms Claimed

Claims 1-4, 14 and 18 are directed to “crystalline form of Avasopasem manganese designated as Form AM1”. Applicant discloses that Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Avasopasem manganese Form AM1. Specification at page 4, [0016].

As known in the art, the set of lines, their location, and relative intensity, obtained for an X-ray powder pattern of a crystalline phase, is characteristic for that phase and represents a unique fingerprint. Solid State Characterization of Pharmaceuticals (R.A. Storey et al., eds., 2011) (see Storey at page 63, “A particular use of powder diffraction in this context is to identify polymorphs and polymorph mixtures quickly either in high-throughput or smaller crystallization experiments. This is because the powder pattern is such a unique fingerprint”); see also, Storey at page 67.

Accordingly, specification Fig. 1 is a unique fingerprint of claim 1 avasopasem manganese Form AM1 that differentiates Form AM1 from all other crystalline forms of avasopasem manganese (such as, amorphous forms, solvates, hydrates, etc.).

As such, each of claims 1-4, 13, 14, and 18 are reasonably interpreted, consistently with the specification, as directed to the exact same crystalline form, that is Avasopasem manganese designated as Form AM1 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1. MPEP § 2111. Note that the claim 18 term “medicament” is broadly and reasonably interpreted to read upon a one-component composition consisting of only the claim 1 crystalline Form AM1. MPEP § 2111. Neither claim 18 nor the specification require that a “medicament” comprise additional materials or components other than the claimed crystalline form itself. See, specification at page 3, [0013]; Id. at page 22, [00114].

Similarly, claims 5-8, 21 and 24 are interpreted as directed to the exact same thing, that is Avasopasem manganese designated as Form AM2 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 2. Specification at page 4, [0017].

Similarly, claims 9-12, 25 and 28 are interpreted as directed to the exact same thing, that is Avasopasem manganese designated as Form AM4 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 4. Specification at page 4, [0019].

Claim Objections

Duplicate Claims

When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Applicant is advised that should base claim 1 be found allowable; its duplicate will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. MPEP § 608.01(m).

Dependent claims 2-4, 13, 14 and 181 are objected to as duplicative of claim 1 upon which they depend. MPEP § 608.01(n)(III). As discussed above in Claim Interpretation, each of claims 1-4 and 14 are interpreted, consistently with the specification, as directed to the exact same thing, that is Avasopasem manganese designated as Form AM1 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1. MPEP § 2111. There is no difference between the subject matter of claim 1 and the subject matter of claims 2-4, 13, 14 and 18. As such, claims 2-4, 13, 14 and 18 are duplicates of claim 1 because they are so close in content that they both cover the same thing, despite a slight difference in wording.

Dependent claims 6-8, 21 and 24 are objected to as duplicative of claim 5 upon which they depend for the same reasons discussed above. MPEP § 608.01(n)(III). There is no difference between the subject matter of claim 5 and the subject matter of claims 6-8 and 21. As such, claims 6-8, 21 and 24 are duplicates of claim 5 because they are so close in content that they both cover the same thing, despite a slight difference in wording.

Dependent claims 10-12, 25 and 28 are objected to as duplicative of claim 9 upon which they depend for the same reasons discussed above. MPEP § 608.01(n)(III). There is no difference between the subject matter of claim 9 and the subject matter of claims 10-12, 25 and 28. As such, claims 10-12, 25 and 28 are duplicates of claim 9 because they are so close in content that they both cover the same thing, despite a slight difference in wording.

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 2-4, 13, 14 and 182 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of claim 1 upon which they depend. MPEP § 608.01(n)(III). As discussed above in Claim Interpretation, each of claims 1-4 and 14 are interpreted, consistently with the specification, as directed to the exact same thing, that is Avasopasem manganese designated as Form AM1 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1. MPEP § 2111. There is no difference between the subject matter of claim 1 and the subject matter of claims 2-4, 13, 14 and 18. As such, claims 2-4, 13, 14 and 18 fail to further limit the subject matter of claim 1 upon which they depend.

Dependent claims 6-8, 21 and 24 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of claim 5 upon which they depend for the same reasons discussed above. MPEP § 608.01(n)(III). There is no difference between the subject matter of claim 5 and the subject matter of claims 6-8, 21 and 24. As such, claims 6-8, 21 and 24 fail to further limit the subject matter of claim 5 upon which they depend.

Dependent claims 10-12, 25 and 28 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of claim 9 upon which they depend for the same reasons discussed above. MPEP § 608.01(n)(III). There is no difference between the subject matter of claim 9 and the subject matter of claims 10-12, 25 and 28. As such, claims 10-12, 25 and 28 fail to further limit the subject matter of claim 9 upon which they depend.

Claim Rejections - 35 USC § 102 (AIA )

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.

(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.

35 U.S.C. § 102(a)(1)/(2) over J. Keene et al., WO2018/152353 (2018) (“Keene”)

Claims 1-4, 13, 14, and 18, directed to avasopasem manganese Form AM1, are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by J. Keene et al., WO 2018/152353 (2018) (“Keene”); or alternatively,

Claims 5-8, 21 and 24, directed to avasopasem manganese Form AM2, are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by J. Keene et al., WO 2018/152353 (2018) (“Keene”); or alternatively,

Claims 9-12, 25 and 28, directed to avasopasem manganese Form AM4, are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by J. Keene et al., WO 2018/152353 (2018) (“Keene”).

Reasons Why This § 102 Rejection Is in the Alternative

The § 102 rejection of claims 1-14, 18, 21, 24, 25 and 28 is in the alternative because, as discussed in more detail below, Keene does not disclose the x-ray powder diffraction pattern for the crystalline form of avasopasem manganese (GC4419) isolated. Rather in Fig. 12, Keene discloses a three-dimensional drawing, based on interpretation of the data generated from single crystal X-ray analysis, which drawing cannot be converted to a powder x-ray diffractogram by the Office. Thus, the crystal form disclosed by Keene cannot be compared to the instant claims. However, rational is provided below regarding why one of the instantly claimed crystalline forms of avasopasem manganese (i.e., one of AM1, AM2, or AM4) is almost certainly the same as the crystalline form of avasopasem manganese disclosed in Keene Fig. 12. MPEP § 2112(V) (citing In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977).

Teachings of Keene

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].3 Keene’s discloser is based on a single crystal x-ray analysis. Keene at page 4, lines 1-2. The 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) 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 polymorphic form of avasopasem manganese (GC4419). 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.

Here, claims 1-14, 21, 24, and 28 are directed to Forms AM1, AM2, AM3 in the alternative. One of these forms is almost certainly the same polymorphic form of avasopasem manganese (GC4419) as taught by Keene because rational is presented above (in view of Keen’s slow crystallization), that Keene teaches the thermodynamically stable polymorphic form of avasopasem manganese (GC4419).

The specification working examples, as discussed in Claim Interpretation above, show that AM1 or AM2, more likely AM1 is the same thermodynamically stable polymorphic form of avasopasem manganese (GC4419) taught by Keene Fig. 12. This is based on crystallization rates and interconversion of AM1 or AM2 into one another.

Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the examiner presents evidence or reasoning to show inherency, the burden of production shifts to the applicant. MPEP § 2112(V) (citing In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977). This is a procedural burden shifting. The requirement that the prior art necessarily teaches the alleged inherent (functional) element still remains. MPEP § 2112(IV). However, the burden is shifted to Applicant to demonstrate the alleged inherent element is not necessarily present in the cited prior art. Stated differently, when the examiner "has reason to believe" that the prior art reference inherently teaches the functional limitation (in this case x-ray powder diffractogram data), the burden shifts to the patent applicant to show that the functional limitation cannot be met by the prior art reference. MPEP 2112(V), see also, In re Schreiber, 128 F.3d 1473, 1478 (Fed. Cir. 1997); In re Chudik, 674 F. App'x 1011, 1012 (Fed. Cir. 2017) (both citing In re Swinehart, 439 F.2d 210, 212, 58 C.C.P.A. 1027 (C.C.P.A. 1971)). Where the Patent Office has reason to believe that a functional limitation asserted to be critical for establishing novelty in the claimed subject matter may, in fact, be an inherent characteristic of the prior art, it possesses the authority to require the applicant to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on. In re Schreiber, 128 F.3d 1473, 1478 (Fed. Cir. 1997) (citing In re Swinehart, 58 C.C.P.A. 1027, 439 F.2d 210, 212, 169 USPQ 226, 228 (CCPA 1971) (emphasis added).

Here, the burden is shifted to Applicant to demonstrate that the claimed forms (either AM1, AM2, and/or AM4) differ from the crystalline form of avasopasem manganese (GC4419) taught by Keene. 4

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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under AIA 35 U.S.C. 103(a) 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 15, 17, 20, 22, 23, 26 and 27 are rejected 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”).

Note that (as in the above § 102 rejection) claim pair 15 and 17 (directed to compositions of AM1) is alternatively rejected versus claim pair 22 and 23 (directed to compositions of AM2) versus claim pair 26 and 27 (directed to compositions of AM4) for the same reasons discussed above for the § 102 rejection. The § 103 rejection of these claims is made in the alternative because, as discussed in more detail below, Keene does not disclose the x-ray powder diffraction pattern for the crystalline form of avasopasem manganese (GC4419) isolated. Rather in Fig. 12, Keene discloses a three-dimensional drawing, based on interpretation of the data generated from single crystal X-ray analysis, which drawing cannot be converted to a powder x-ray diffractogram by the Office. Thus, the crystal form disclosed by Keene cannot be compared to the instant claims.

Teachings of Keene

Keene is discussed in detail above. 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 unit dose formulations and pharmaceutical compositions comprising the compounds described herein, typically together with a pharmaceutically acceptable carrier or excipient. Keene at page 46, [00152]. Keene teaches the pharmaceutical compositions include any of the compounds set forth in Table I (of which the first listed compound is GC4119). Keene at page 46, [00152], see also Keene at page 101, Table I.

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]. Claims 15, 17, 22, 23, 26 and 27 are directed pharmaceutical compositions comprising Forms AM1, AM2, or AM3 and a pharmaceutically acceptable excipient.

As discussed in the § 102 rejection above, Keene effectively teaches crystalline avasopasem manganese (GC4419) by slow crystallization from water after dropwise addition of ethanol, per the method of Riley. Keene thus likely teaches the thermodynamically stable polymorphic form of avasopasem manganese (GC4419). 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.

As discussed in detail in the § 102 rejection above, one of the instantly claimed forms (AM1, AM2, or AM3) is almost certainly the same crystalline form of avasopasem manganese (GC4419) as taught by Keene because rational is presented above (in view of Keen’s slow crystallization), that Keene teaches the thermodynamically stable polymorphic form of avasopasem manganese (GC4419). MPEP § 2112(V) (citing In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977).

Here, the burden is shifted to Applicant to demonstrate that the claimed forms (either AM1, AM2, and/or AM4) differ from the crystalline form of avasopasem manganese (GC4419) taught by Keene. MPEP § 2112(V) (citing In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977).

Differences between Keene and the Claims

Keene teaches each and every element of claims 15, 17, 20, 22, 23, 26 and 27. Keene differs only to the extent that one of ordinary skill must choose 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. Keene at page 2, [0004].

H.G. Brittain, in Polymorphism in Pharmaceutical Solids (H.G. Brittain ed., 2nd ed., 2009) (“Brittain”).

Brittain teaches that once the phase space of a substance has been determined, and the scope of possible polymorphic forms is established, it becomes critical to determine the boundaries of stability for the different polymorphic forms and how they might be interconverted. At the very least, one must determine which crystal form is the most stable state, because unless mitigating circumstances dictate otherwise, that form would be the one to be chosen for continued development. Brittain at page 2.

Brittain further 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.

Obviousness Rational

Claim 20 is obvious over Keene and claim pair 15 and 17 (directed to compositions of AM1) are alternatively obvious versus claim pair 22 and 23 (directed to compositions of AM2) versus claim pair 26 and 27 (directed to compositions of AM4) are obvious over Keene, because 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. One of ordinary skill thereby meets each and every limitation of claim 20 and each and every limitation of claim pair 15 and 17 (directed to compositions of AM1), or alternatively the limitations of claim pair 22 and 23 (directed to compositions of AM2) or alternatively those of claim pair 26 and 27 (directed to compositions of AM4) under an inherency analysis as discussed in detail above in the § 102 rejection.

One of ordinary skill is so motivated because this is the express utility taught by Keene. Keene at page 2, [0004]. One of ordinary skill is further motivated to employ this crystalline form because Keene teaches it preparation by slow crystallization from water after dropwise addition of ethanol, which is thus the thermodynamically stable polymorphic form of avasopasem manganese (GC4419). If the compound exhibits multiple crystal forms, then the thermodynamically more stable polymorphs will typically be created in the slow crystallizations. Brittain at page 87 (see also pages 77-78). In this regard, Brittain teaches that one must determine which crystal form is the most stable state, because unless mitigating circumstances dictate otherwise, that form would be the one to be chosen for continued development. Brittain at page 2.

Conclusion

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ALEXANDER R. PAGANO
Examiner
Art Unit 1692

/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692

1 As discussed in Claim Interpretation, the claim 18 term “medicament” is broadly and reasonably interpreted to read upon a one-component composition consisting of only the claim 1 crystalline Form AM1. MPEP § 2111. Neither claim 18 nor the specification require that a “medicament” comprise additional materials or components other than the claimed crystalline form itself. See, specification at page 3, [0013]; Id. at page 22, [00114].

2 See footnote 1.

3 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).

4 It is important that a patent claim not be issued for the same crystal form of a compound already in therapeutic development. For example, Weekly teaches that the enantiomer of M40403, named GC4419 (Scheme 1), has entered phase 2 trials for protection against chemoradiation-therapy-induced oral mucositis (NCT02508389). C. Weekly et al., 56 Inorganic Chemistry, 6076-6093 (2017) (“Weekly”) (see, Weekly at page 6077, col. 1). Weekly cites C. Anderson et al., Phase 1b/2a Trial of Superoxide (SO) Dismutase (SOD) Mimetic GC4419 to Reduce Chemoradiation Therapy−Induced Oral Mucositis (OM) in Patients With Oral Cavity or Oropharyngeal Carcinoma (OCC), 94 Int. J. Radiat. Oncol., Biol., Phys., 869-870 (2016) (“Anderson”). The GC4419 tested in clinical trials was almost certainly prepared, at least initially, in crystalline form. In this regard, Datta teaches that most marketed pharmaceuticals consist of molecular crystals. S. Datta et al., 3 Nature Reviews | Drug Discovery, 42-57 (2004) (“Datta”) (Datta at page 42, col. 1, “[m]ost marketed pharmaceuticals therefore consist of molecular crystals”).