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
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Claim Status
Claims 10-15 were examined upon RCE entry in the prior Office Action.
Upon amendment entry, Claim 10 was amended.
Claims 10-15 are pending examination.
Priority
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statements
Examiner acknowledged the IDS(s) filed 03/22/2024 in the Office Action of 08/05/2024.
Drawings
Examiner acknowledged the drawings filed 09/28/2022 in the Office Action of 08/05/2024.
Examiner Responses to Amendments/Arguments
The issues raised in the Office Action are addressed in 10/08/2025 and below:
I. Response to 35 USC § 103 Claim Rejections -
Claims 10-15 rejected over Rajiv Bhushan et al (US 2010/0035992 A1; hereinafter "App’992") in view of Lynne Bannen et al. (US 8,367,667 B2; hereinafter "Patent’667").
Applicant’s arguments, filed 10/08/2025, with respect to the claims have been fully considered but they are not persuasive for the following reason(s):
Applicant argues: “…Bhushan et al discuss the effects of the chelating agent on inflammation. However, the inventiveness of the present invention lies not in the effect on inflammatory markers, but the establishment of a safe and effective dose of EDTA that may be administered via inhalation…”
Applicant further argues “The use of chelating agents had already been tested as inhaled formulations for lung conditions before the publication of Bhushan et al and found to have negative effects. Wood et al (1980) pre-dates Bhushan et al and Wood et al (1980) found that when administering EDTA to lungs, adverse effects were generated in the subject. The mere mention at paragraphs [0233]-[0234] of Bhushan et al that the compositions could be inhaled does not provide any direction as to how to actually achieve such delivery in humans.
Examiner disagrees.
Applicant is correct that App’992 states in para. [0233], “formulations for nasal administration can be prepared with standard excipients, e.g., as a solution in saline, as a dry powder, or as an aerosol and may be administered by a metered dose inhaler (MDI), dry powder inhaler (DPI) or a nebulizer.” This indicates this type of formulation is known to exist in the field.
In Example 1, paras. [0237]-[0239], a composition of EDTA and MSM was administered via nasal route. The use of Wood (as indicated by the Applicant) is correct, EDTA – alone - would have an adverse effect on the lungs, but App’992 does not state this. App’992 discloses the nasal composition in a specific form of MSM (a sequestering agent) with EDTA. This combination is known in the art, as seen in App’992 because of its ability to use MSM to enhance and penetrate biological membranes.
In the Instant Specification (para. [0021]), in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., inhaled ethylenediaminetetraacetic acid (EDTA)) is recited in the Specification as CaEDTA for the chelating agent. As such, the prior art combination discloses the specific form with the use of a sequestering agent that is able to permeate the lungs. This is suitable for treating heavy metal poisoning (like lead) without removing essential calcium from the body, unlike pure EDTA (under BRI is recognized as the base acid) or its sodium salts (Na2EDTA) which can diminish calcium, causing hypocalcemia. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues, “The examiner asserts that conversion of a dose in, for example, rats, to a dose in humans is routine and uses Reagan-Shaw et al (2007) to support this contention. However, the advice in Regan-Shaw et al (2007) is in relation to converting oral doses. This cannot be applied to inhaled doses, which has different considerations.”
Examiner disagrees.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Additionally, the Regan-Shaw prior art (FASEB J. 2008 Mar; 22,3,:659-61) does refer to dosage conversion between species, but so does the art of Patent’667 (US 8,367,667 B2). Patent’667 discloses in col. 36, lns. 19-37: “The compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.”
This indicates that long before the effective filing date of this application, the artisan knew how to obtain optimal doses of drugs for human inhalation, which is also seen in Patent’667 on col. 30, lns. 40-63. The prior art combination discloses the specific form with the use of a sequestering agent that is able to permeate the lungs. This is suitable for treating heavy metal poisoning (like lead) without removing essential calcium from the body.
The functional language is met for the claims. The Applicants arguments are not persuasive.
The 35 USC § 103 rejection over Claims 10-15 using Bhushan et al (US 2010/0035992 A1; hereinafter "App’992") in view of Bannen et al. (US 8,367,667 B2; hereinafter "Patent’667") is maintained.
II. Maintained Rejections -
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Joint Inventors
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Rajiv Bhushan, et. al (US 2010/0035992 Al; hereinafter “App’992”) and in view of Lynne Bannen, et. al (US 8,367,667 B2)(hereinafter “Patent’667”) and further in view of S. Reagan-Shaw, et al. in “Dose translation from animal to human studies revisited” (pub’d 10/17/2007; hereinafter “Reagan-Shaw”).
With respect to Claim 10, App’992 teaches a method of treating inflammation in the lung (abstract, para. [0061]) by administering doses (…formulations for inhalation and therefore be adapted to be administered via a metered-dose inhaler…where upon activation a fixed dose is released in aerosol form, paras. [0233]-[0234]);
wherein each of the one or more doses of the EDTA is administered over a period of no more than 2h (lipopolysaccharide was used as a endotoxin for the promotion of pro-inflammatory cytokine secretion) … A 20 μL composition of MSM and EDTA (e.g., 5.4% MSM + 2.6% EDTA) was then administered via the nasal route 15 minutes after the LPS-injection and then after every two hours; paras. [0237]-[0238]).
App’992 fails to teach from 37.5 mg/dose to 300 mg/dose of inhaled EDTA wherein the EDTA is at a concentration of at least 50 mM.
However, App’992 teaches that the dosing is dependent on the kg of body weight, as well as how to go from animal to human. Something commonly done in the art. Modifying the dose based on body weight would make dosing a result effective variable since the concentration depends on the body weight. As such, dosage optimization is conducted as a result-effective variable that will alter the rate of reactivity, the production of by-products and the final yield of desired product depends on the ratio/desired starting measurements.
Although the examples in the art are for rats, App’992 does teach that humans are a preferred patient population such that once could at once envisage humans. Also in App’992 publication (para. [0214]) “the dosage regimen will depend on a number of factors that may readily be determined. One of ordinary skill may readily determine optimum dosages, dosing methodologies, and repetition rates”.
This is substantiated by the additional reference of Reagan-Shaw which indicates this conversion is common in this field of endeavor, the extrapolation of animal dose to human dose can be correctly performed (Reagan-Shaw: pg. 660, col. 1, full para. 1, Figure 1 & Table 1).
For that reason, though Example II and III do teach different concentrations of EDTA used in conjunction with a permeability enhancer to allow the EDTA to penetrate the epithelial membranes of the inflamed lungs (which the Instant Application is silent on), to demonstrate reduction in inflammation (para. [0237] to [0241]); Example I also teaches a composition can also be administered to the subject via the nasal route 15 minutes after the LPS-injection and then after every two hrs. This demonstrates that when the inflammatory response is triggered, it leads to the release of cytokines and other inflammatory mediators, and the nasal administration of this EDTA formulation with an enhancer reduced inflammation. It also teaches that the nasal route is effective and has been demonstrated through variables that are result effective and can be optimized according to dosing methodologies.
Therefore, it would been obvious to one of ordinary skill in the art to choose the claimed ranges, since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980). According to MPEP 2144.05, optimizing result effective variables is prima facie obvious absent a showing of criticality.
MPEP 2144.05 II.A:
In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”).
See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”)
With respect to claim 11-13 and 15, App’992 continues to teach the treatment of inflammation is associated with a decrease in MMP activity (immunohistochemistry demonstrated the increase in inflammatory and oxidative markers were significantly suppressed by the EDTA and MSM composition. These results indicate that a topical application of an EDTA and MSM composition is effective for inhibiting the activation of NF-KB, MMP-9, and the release of TNF-a, thereby decreasing inflammation; para. [0247]);
wherein the treatment of inflammation results in an increase in FEV (According to the Applicant’s specification on pg. 13, “the term treatment further includes one or more of an increase in anti-inflammatory cytokines, and an increase in lung function, FEV1. This in conjunction with para. [0247] above indicates, inhibition of anti-inflammatory cytokines would logically specify a decrease in inflammation and an increase in lung function (which is the FEV);
wherein the treatment of inflammation is associated with a decrease in the production of hydroxyl radicals (Removal of harmful stimuli often involves the production of compounds, such as reactive oxygen species (hydroxyl radicals), which are toxic to the body. Hence, if left unchecked, inflammation leads to a pathological cycle of destruction and healing of the tissue, which increases the oxidative stress of the entire body system; paras. [0048]-[0054]);
wherein the EDTA is CaEDTA (pharmacologically acceptable EDTA salts may be advantageously used…calcium disodium EDTA. EDTA has been widely used as an agent for chelating metals in biological tissue and blood, para. [0127]).
With respect to claim 14, App’992 teaches the methods and compositions for the treatment of inflammation and disorders, diseases, and adverse conditions, i.e., pathologies, caused by or otherwise associated with inflammatory processes.
App’992 fails to teach wherein the EDTA is combined with tris-(hydroxymethyl)-aminomethane (TRIS).
Patent’667 does teach wherein an acceptable adjuvant or method of modulating the activity of receptors for the treatment, prevention, or amelioration of one or more symptoms of disease is…tris-(hydroxymethyl)-aminomethane (TRIS) (col. 28, lns. 13-15). This is combined, resuspended and cultured (Angiotensin converting enzyme inhibitors" or "ACE inhibitors"
representative group; (col. 150, lns. 53-62; col. 160, lns. 4-8; col. 161, lns. 25-27) .
It would therefore be obvious to modify App’992’s method and composition of a metered-dose inhaler with EDTA and combine with Patent’667 adjuvant pharmaceutical composition (col. 20, lns. 40-41) which aids in immune dysfunction by way of administration of an oral inhaler (col. 30, lns. 50-57). The advantage of a metered-dose inhaler able to reduce the inflammatory response in patients with lung infections or inflammation would prolong quality of life for patients suffering from immunological dysfunction.
Also, based on the teachings and language of App’992, one could readily extend the range of “at least 50 mM of the EDTA concentration” under the Broadest Reasonable Interpretation to mean “concentrations above 50 mM which would lead to an overlapping range with the prior art. See MPEP 2144.05 incorporated by reference herein.
Overlapping ranges:
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of “50 to 100 Angstroms” considered prima facie obvious in view of prior art reference teaching that “for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms].” The court stated that “by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.”).
Close ranges:
Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. “The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties.”).
Above, Examiner made the case that an overlapping range exists. In addition, App’992’s teachings at para. [0242] can be considered a close range. Since the limitation “at least 50 mM” is met by the 70 mM, a higher concentration of EDTA can be diluted to the concentration of the claimed language “at least 50 mM”. Also since concentration is a result-driven process, it can be optimized by one skilled in the art to the overlapping range based on the logic and/or a close range based on the prior art.
Conclusion
Claims 10-15 are rejected.
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 Josmalen M. Ramos-Lewis whose telephone number is (571)272-0084. The examiner can normally be reached M-F 9:30-5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621 01/15/2026