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, 20-23 and 25-27 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:
PNG
media_image1.png
200
400
media_image1.png
Greyscale
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, 13-15, 17 and 20 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.
Similarly, claims 5-8, and 21-23 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, and 25-27 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, and 14 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, 13 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, and 14. As such, claims 2-4, 13, and 14 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, and 21 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, and 21 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, and 25 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, and 25. As such, claims 10-12 and 25 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 and 14 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, 13 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, and 14. Stated differently, claims 2-4, 13 and 14 recite further words and numbers, but the subject matter claimed is still the same as claim 1; thus claims 2-4, 13, and 14, while reciting further words and numbers do not in any way limit the subject matter of base claim 1. As such, claims 2-4, 13, and 14 fail to further limit the subject matter of claim 1 upon which they depend.
Similarly, dependent claims 6-8 and 21 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 and 21. As such, claims 6-8 and 21 fail to further limit the subject matter of claim 5 upon which they depend.
Similarly, dependent claims 10-12 and 25 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 and 25. As such, claims 10-12 and 25 fail to further limit the subject matter of claim 9 upon which they depend.
Applicant’s Argument
With respect to the duplicative claim objection and § 112(d) rejection, Applicant argues that each of the present dependent claims satisfies § 112(d) by incorporating every limitation of its base claim and then specifying additional structural or compositional limitations that narrow its scope.
This argument is not persuasive for the following reasons. As discussed above in Claim Interpretation, each of claims 1-4, 13 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. Thus, each of these claims, per § 112(d) must exhibit the X-ray powder diffraction pattern substantially as depicted in Figure 1. As discussed in Claim Interpretation, 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. For example, changing the percentage of polymorphic and/or amorphous forms or the solvate of the claim 1 Avasopasem (see claims 12-14) would distort the x-ray diffraction pattern of Fig. 1. Since by definition (under § 112(d)) the crystalline form of AM1 of claims 12-14 must exhibit the X-ray powder diffraction pattern substantially as depicted in Figure 1, it is not seen how a further limitation is specified in claims 12-14.
The same argument applies to the other rejected claims.
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 and 14, 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 and 21, 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 and 25, 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, 21, and 25 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):
PNG
media_image2.png
200
400
media_image2.png
Greyscale
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.
The cited reference, D. Riley et al., 59 Advances in Inorganic Chemistry, 233-263 (2007) (“Riley”), teaches that crystalline M40401-(PF6)2:
PNG
media_image3.png
200
400
media_image3.png
Greyscale
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 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 Specification working Example 1 (Form AM1) and Example 2 (Form AM2) teach slow recrystallization (two days) from dichloromethane and tetrahydrofuran as respective solvents. Specification at page 24. 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.
Here, claims 1-14, 21, and 25 are directed to Forms AM1, AM2, AM3 in the alternative, where either of claimed Form AM1 or Form AM2 is likely the same polymorphic form as disclosed by Keene. This is because both Keene and the specification Examples 1 and 2 (Forms AM1 and AM2) employ slow crystallization (over a period of days) likely leading to the more thermodynamically stable crystalline form. In sum, one of claimed crystalline forms is likely 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).
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 properly shifted to Applicant by a preponderance of evidence to demonstrate that the claimed forms (either AM1, AM2, and/or AM4) differ from the crystalline form of avasopasem manganese (GC4419) taught by Keene. 3
See non-binding, non-precedential opinion in Ex Parte Reddy, Appeal No. 2009-000439, 10/505,826 (BPAI 2009). In Ex parte Reddy, claim 1 recited:
1. A crystalline Form X of 2-[[[4-(3-methoxypropoxy)-3- methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole sodium having an X-ray powder diffraction pattern substantially as depicted in Figure 1.
Ex parte Reddy at page 1. The Examiner cited Example 33 of reference Souda “wherein the compound was crystallized from ether”. Ex parte Reddy at page 5. The board in Ex parte Reddy noted that Souda’s process of preparing its crystals is not identical to that disclosed in the Specification for preparing the crystalline form X recited in claim 1. However, the processes have significant similarities. Ex parte Reddy at page 13. The board held that given the similarities between Appellants’ and Souda’s processes, the fact that both processes produce crystals, and the fact that the compounds have the same chemical formula, a preponderance of the evidence supports the Examiner’s finding that Souda’s preparation of crystalline rabeprazole sodium contains at least some of the form X required by claim 1 shifting the burden of production to Applicant. Ex parte Reddy at page 14 (citing In re Best, 562 F.2d at 1255).
Applicant’s Argument
Applicant argues that the § 102 rejection appears to rely on speculation that one of the claimed crystalline forms (Form AM1, AM2, or AM4) is ‘almost certainly the same’ as the form of GCT4419 depicted in Keene's Figure 12. (Office Action at 11.) Applicant argues that that reasoning fails to meet the strict standard for inherent anticipation. Moreover, the rejection is presented "in the alternative," asserting that a single reference could anticipate three distinct crystalline forms characterized by three different XRPD fingerprints. Applicant argues that a single prior art disclosure cannot simultaneously anticipate mutually exclusive structural definitions; the need for alternative theories underscores the absence of any inevitable identity required for inherency.
This argument is not persuasive for the following reasons. Here, the burden of production is properly shifted to Applicant to demonstrate the claims are not anticipated. It is noted that Applicant provides no evidence or argument that Keene does not disclose the same crystalline form claimed. Rather, Applicant argues that the Examiner has not met its burden. Here, the Examiner has no choice but to reject in the alternative because the Office does not have the experimental tools to determine which form Keene actually discloses. For example, if the instant claims were only directed Form AM1, the rejection would be the same. Since the burden is properly shifted, this argument is not persuasive.
Applicant argues that the inference drawn from Keene's citation to Riley is misplaced because Riley describes the crystallization of an entirely different complex, M40403-(PF6)2, having a distinct counterion and lattice environment. The behavior of that compound cannot establish the polymorphic outcome for GC4419 and therefore provides no evidence that Keene obtained any of the claimed forms.
This argument is not persuasive because 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]. The cited reference, D. Riley et al., 59 Advances in Inorganic Chemistry, 233-263 (2007) (“Riley”), teaches that crystalline M40401-(PF6)2:
PNG
media_image3.png
200
400
media_image3.png
Greyscale
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.
Applicant argues that the fact that a solid may form under "slow" crystallization conditions does not identify it as thermodynamically stable, nor does it indicate which form will result and the specification establishes that multiple polymorphs of Avasopasem manganese are accessible under similar kinetics but differing solvent and drying regimes. Consequently, the assumption that Keene's "slow crystallization" must yield a single, thermodynamically stable form identical to Applicant's Form AMI is not supported by the evidence.
This argument is not persuasive because the above rejection’s basis is not that Keene’s crystalline form is the definitely most stable thermodynamic form nor that there is a 100% probability that Keene’s crystalline form is one of the claimed forms. The basis of the § 102 rejection is that, under a preponderance of evidence, the burden is properly shifted to Applicant demonstrate otherwise; for one, because the Office does not have the experimental tools and such experiments should be relatively straightforward for Applicant.
As noted above in footnote 3, it is important that a patent claim should not be issued for the same crystal form of a compound already in therapeutic development. However, Applicant argues that such is irrelevant to a § 102 inquiry. In response, the concept of burden shifting, as stated in In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977), is for the very case where an examiner determines that a claimed product appears substantially identical to the prior art, the burden of production shifts to the applicant. In other words, In re Best provides a check to ensure that a patent claim will not issue to a compound known in the art.
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):
PNG
media_image2.png
200
400
media_image2.png
Greyscale
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.
Applicant’s Argument
Applicant argues that the present specification demonstrates that the crystalline behavior of avasopasem manganese does not follow a single kinetic or thermodynamic trend: Forms AM1, AM2, and AM4 can each arise under both slow and rapid crystallizations, depending on solvent composition, water activity, and drying regime. Thus, Brittain's general discussion cannot render any of these discrete polymorphs predictable or obvious to try.
This argument is not persuasive because the § 103 rejection already asserts that Keene’s crystalline form is the same as that claimed. The § 103 rejection is made because Keene does not teach the further composition and method limitations of claims 15, 17, 20, 22, 23, 26 and 27.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER R PAGANO whose telephone number is (571)270-3764. The examiner can normally be reached 8:00 AM through 5:00 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
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.
3 It is important that a patent claim should 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”).