DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/15/2025 is in compliance with the provisions of 37 C.F.R. 1.97. All references cited in this IDS have been fully considered.
Amendments
Claim 1 has removed the parenthetical language, no longer recites the approximation “about” in the enzyme dose, and limits the dosage range to 0.05 mg/kg to 1 mg/kg.
Claims 3-22 have been amended to depend from claim 1.
Drawings
Previous objection to the drawings
Figure 3 was objected to because the text contained therein was smaller than the minimum required height. Applicant has amended the drawing such that the text size is larger than the minimum required height.
Figures 6-10 and 14-17 were objected to for improperly number partial views. Applicant’s corrections to these figures is not sufficient to overcome the objection to the drawings. Moreover, the quality of FIGS. 8A-8D has been reduced such that the text is no longer legible.
Accordingly, the objection to the drawings is maintained.
Maintained objection to the drawings
The drawings are objected to for the following reasons.
Figures 6-10 and 14-17 are objected to because they contain improperly numbered partial views. Per the drawing standards, partial views must be identified by the same number followed by a capital letter (37 CFR 1.84(u)(1)). Instead, each partial view in the above identified figures is identified by only a capital letter. These figures should be separated and amended, for example, to read Fig. 6A, Fig. 6B, Fig. 6C, Fig. 6D, etc. In the interest of compact prosecution, if applicant wishes to keep each partial view together rather than separating each view, the lettering should be removed. However, in the interest of promoting the clarity and legibility of the drawings, it is recommended that each view be separated in order to maximize the size of each panel.
The text in FIGS. 8A-8D is not of sufficient quality to be legible when reproduced.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
Applicant was previously required to provide a substitute specification which inserts the required incorporation-by-reference paragraph. Applicant has amended the specification to recite the correct name and size of the sequence listing files. Moreover, applicant has provided a statement that the replacement sequence listing contains no new matter (Remarks, par. 3).
Claim Objections
Previous objection to the claims
Claims 4-22 were objected to under 37 CFR 1.75(c) as being in improper form. Applicant has amended each of these claims such that they depend from claim 1.
Accordingly, the objection to claims 4-22 has been withdrawn.
New objections to the claims
Claim 6 is objected to because the unit “mg/mL” should be added after “about 1”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Previous rejections under 35 U.S.C. § 112
RE: Rejection of claims 1-3 under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint, regards as the invention.
Claim 1 was considered to be indefinite because it recited an approximation (“about”) without sufficient context to determine the scope of the approximation. In response, applicant has removed this approximation from the language of claim 1.
Claim 1 was further rejected because it used a parenthetical which rendered the scope of the claim unclear. Applicant has amended the claim such that the native human CGL amino acid sequence is clearly defined as the sequence of SEQ ID NO: 1.
Claims 2-3 were rejected because they inherited the indefinite language of claim 1.
Because applicant has made the appropriate changes to claim 1, the rejection of claims 1-3 is withdrawn.
New grounds of rejection under 35 U.S.C. § 112
Claims 5-6, 10-12, and 20-22 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint, regards as the invention.
Claims 5-6, 10-12, and 20-22 recite the approximation “about”. In determining the range encompassed by the term "about," one must consider the context of the term as it is used in the specification and claims of the application (MPEP § 2173.05(b)(III)(A)). In this case, the context of this term (enzyme concentration, dosing amount, and total plasma homocysteine levels) has been considered in light of the specification. The specification does not provide any way of ascertaining what applicant considers to be encompassed by the phrase “about”. For example, is 14 µM “about 15 µM”? What about 10 µM?
Because it is not possible to ascertain the scope of the claimed range, the claimed range has been examined for prior art purposes for the recited amounts.
Claims 10-12 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 has been amended to narrow the dosage range to “0.05 mg/kg to 1 mg/kg”. Claims 10-12 broaden, rather than narrow, the scope of claim 1 because they encompass values not contained within this range.
As discussed above, claims 10-12 recite the approximation “about”. This approximation allows for values which are higher or lower than the recited value. As such, these claims encompass values which are greater than 1 mg/kg (and depending on the meaning of “about”, values which are less than 0.05 mg/kg).
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
As discussed in the rejection under 35 U.S.C. § 112(b), these claims have been examined without respect to the approximation because it is not possible to ascertain what values are encompassed by this range.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Previous rejection under 35 U.S.C. § 103
RE: Rejection of claims 1-3 under 35 U.S.C. 103 as being unpatentable over Georgiou et al. (US 2018/0326025 A1; cited in IDS filed on 12/18/2023).
Claims 1-3 were previously rejected as being obvious over Georgiou, which teaches methods for the treatment of homocystinuria or hyper-homocysteinemia (abstract). Applicant argues that the instant claims are non-obvious over the teachings of Georgiou because Georgiou teaches dosages ranging from about 0.5 mg/kg to about 750 mg/kg and this very broad range cannot be said to create a reasonable expectation of success in using an enzyme dose at the extreme low end of the disclosed range and even lower beyond that. Additionally, applicant argues that dosing CBS KO mice subcutaneously at 1.0 mg/kg, 3.0 mg/kg, or 10.0 mg/kg, significantly increased survival when compared to vehicle and “there was no observed correlation between the dose level and percent survival…suggesting that the claimed enzyme may be effective at extending survival at doses lower than 1.0 mg/kg” (Remarks, p. 8, par. 3).
Applicant’s argument has been fully considered but is not sufficient to overcome the rejection of record for the following reasons.
As noted in the rejection of record, Georgiou teaches an identical method of treating a subject having or at risk of developing homocystinuria or hyperhomocysteinemia ([0064]; claims 26-27) by administering an identical enzyme (mutant 3; hCGL-E59I-S63L-L91M-R119D-K268R-T311G-E339V-I353S). Georgiou teaches a dosage range (about 0.5 mg/kg to about 750 mg/kg) which overlaps with the instantly claimed range of 0.05 mg/kg to 1 mg/kg. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (MPEP § 2144.05(I)). Thus, it is not particularly relevant how broad Georgiou’s disclosed range is because the ranges overlap at least when determining prima facie obviousness.
And to the extent that the range is so broad that a reasonable expectation of success is allegedly not present, applicant has substantiated this argument by citing working examples which use values falling entirely within Georgiou’s disclosure (1.0 mg/kg, 3.0 mg/kg, and 10.0 mg/kg). Performing a previously disclosed method with a previously disclosed composition and in a previously disclosed dosage range is not sufficient to overcome the prima facie case of obviousness.
Moreover, it cannot be said that the claimed ranges elicit an unexpected or remarkable result when applicant’s own conclusion is that “there was no observed correlation between the dose level and percent survival as all dose levels resulted in ≥ 80% survival, suggesting that the claimed enzyme may be effective at extending survival at doses lower than 10.0 mg/kg” (Remarks, p. 8, par. 3). This admission is particularly relevant because applicant is arguing that Georgiou’s broad range “cannot be said to create a reasonable expectation of success in using an enzyme dose at the extreme low end of the disclosed range, and even lower beyond that” (Remarks, p. 8, par. 2) while also arguing that their observations at 1.0 mg/kg create suggestions which can be carried forward to doses lower than 1.0 mg/kg. In substantiating their claim to doses which are lower than the tested doses, applicant is using the same expectations which they are arguing are not reasonable when considering the teachings of Georgiou.
Finally, it cannot be said that the particular ranges recited in the claims elicit an unexpected or remarkable result when applicant had argued that the dose level is not relevant to the survival rate.
For at least these reasons, the rejection of record is proper must be maintained. In order to address claims 4-22, which were previously not considered due to their improper multiple-dependence, new grounds of rejection are made below.
New grounds of rejection under 35 U.S.C. § 103
Claims 1-14 and 18-22 are rejected under 35 U.S.C. 103 as being unpatentable over Georgiou et al. (US 2018/0326025 A1; cited in IDS filed on 12/18/2023).
Georgiou et al. (hereinafter Georgiou) is directed to methods and compositions relating to the engineering of an improved protein with homocytienase enzyme activity including compositions and methods for the treatment of homocystinuria or hyper-homocysteinemia (abstract). Georgiou teaches that homocystinuria is a rare disease resulting from an inborn error of metabolism involving sulfur amino acids ([0005]). Patients with homocystinuria often display thromoboembolisms, cognitive impairment, osteoporosis and ocular lens dislocations (Id.). Patients can also suffer from hyperhomocysteinemia, which is a condition in which serum homocysteine (Hcy) concentrations exceed 15 µM (Id.). Currently available treatments for these conditions include methionine-restricted diets as well as high doses of vitamin B6 and betaine to reduce homocysteine levels ([0006]). Although these treatments can be effective for some patients, the responses are variable and thus there is a need to develop a therapy which addresses the need of all patients by reducing blood homocysteine levels back to the normal range (Id.). To address this problem, Georgiou teaches human cystathionine-γ-lyase (hCGL) mutant enzymes with catalytic activity toward homocyst(e)ine for use in methods of treating subjects with homocystinuria or hyperhomocysteinemia ([0008]-[0009]).
Regarding claim 1, Georgiou teaches methods of treating a subject having or at risk of developing homocystinuria or hyperhomocysteinemia ([0064], claims 26-27).
With respect to the method involving the administration of a modified CGL enzyme comprising the various mutations recited in this claim, Georgiou teaches administration of a therapeutically effective amount of various human CGL enzymes including mutant 3 (hCGL-E59I-S63L-L91M-R119D-K268R-T311G-E339V-I353S), which possesses isoleucine at position 59, leucine at position 63, methionine at position 91, aspartic acid at position 119, arginine at position 268, glycine at position 311, valine at position 339, and serine at position 353 ([0010] and [0128])(see below). Georgiou provides working examples involving the administration of this mutant enzyme and teaches that it can provide statistically significant reduction of tHcy within 48 hours ([0208]) and can completely rescue cbs-/- mice from neonatal lethality ([0209])(see p. 1-2 of previously attached “Sequence Alignment.pdf”). Georgiou teaches that these mutations result in improved activity of the CGL enzyme ([0128]).
With respect to the mutations being relative to a native human CGL amino acid sequence, as discussed above, Georgiou teaches that mutant 3 is modified relative to human CGL, as defined by SEQ ID NO: 1 ([0065]). Georgiou’s SEQ ID NO: 1 has 100% identity to applicant’s SEQ ID NO: 1 (see p. 3-4 of previously attached “Sequence Alignment.pdf”). Accordingly, Georgiou teaches a mutant having the same mutations, relative to a native human CGL amino acid sequence.
With respect to the administered amount, Georgiou teaches that the dose may comprise from about 500 micrograms/kg (i.e., 0.5 mg/kg) to about 750 mg/kg body weight ([0199]). This range disclosed by Georgiou overlaps with the claimed range of about 0.05 mg/kg to 1 mg/kg. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (MPEP § 2144.05(I)).
With respect to the dosage frequency of one dose per day to one dose per month, Georgiou does not teach this portion of the dosing regimen. Nevertheless, a person having ordinary skill in the art could have arrived at this dosage frequency through routine experimentation. Georgiou teaches that the CGL enzyme can be administered through repeated dosing ([0130]) and gives specific working examples wherein mice were administered modified CGL every 5 days for 30 days ([0205]). Additionally, Georgiou teaches that the quantity to be administered depends on the subject to be treated, capacity of the subject’s system to utilize the active ingredient and degree of therapeutic effect desired ([0137]). Precise amounts of active ingredient depend on the judgement of the practitioner and are particular to each individual (Id.). For example, suitable regimens include an initial administration followed by repeated doses at one or more hour intervals (Id.). Georgiou teaches that multiple administrations are preferred in order to maintain continuously high serum and tissue levels of modified CGL enzyme and conversely low serum and tissue levels of homocyst(e)ine. Accordingly, a person having ordinary skill in the art would have been prompted to perform this experimentation in order to achieve treatment of homocystinuria or hyperhomocysteinemia. There is no evidence of record that the recited range of one dose per day to one dose per month elicits some unexpected or remarkable result.
With respect to the administered amount being a therapeutically effective amount, as discussed above, Georgiou teaches that the compositions are administered in a therapeutically effective amount ([0137]).
Accordingly, claim 1 is obvious over Georgiou as a result of routine experimentation.
Regarding claim 2, Georgiou teaches that the modified CGL enzyme may be linked to PEG (i.e., one or more PEG units) to increase the hydrodynamic radius of the enzyme and hence increase the serum persistence ([0138], [0153]-[0166]).
Regarding claim 3, as discussed above, Georgiou makes obvious the method of claim 1. Georgiou also teaches that where clinical applications are contemplated, it may be necessary to prepare therapeutic compositions, and the therapeutic compositions may comprise an effective amount of one or more modified CGL enzymes or additional agents dissolved or dispersed in a pharmaceutically acceptable carrier ([0189]-[0190] and [0194]).
Regarding claim 4, as discussed above, Georgiou makes obvious the method of claim 1. Georgiou teaches that the composition may be in a kit comprising a pre-filled ampoule and may be in a container such as a vial ([0200]-[0201]).
Because Georgiou renders obvious the claimed dosage range and teaches that the enzyme may be in a container such as a vial, it would have been obvious to have experimented with various formulations and a person having ordinary skill in the art could have arrived at a formulation of 2 mL of a liquid supplied in a 5 mL vial with a reasonable expectation of success. The claim is to a method of treating a subject by administering the formulation in the recited dosage amount. Therefore, the volume of liquid and type of container would not be expected to have any effect on the ability of the administered composition to treat the subject. There is no evidence that placing Georgiou’s composition in 2 mL of liquid in a 5 mL elicits some unexpected or remarkable result.
Thus, claim 4 is obvious over Georgiou as a result of routine experimentation.
Regarding claims 5-6, as discussed above, Georgiou makes obvious the method of claim 1. Specifically, Georgiou renders obvious the dosage range in terms of mg/kg. The instant claims merely limit the concentration of the enzyme in liquid. When formulating the composition used in Georgiou’s methods, a person having ordinary skill in the art would have been expected to experiment with various formulations and could have arrived at the ranges of “about 1 mg/mL to about 50 mg/mL” and “about 1 [mg/mL] to about 20 mg/mL” with a reasonable expectation of success. The claim is to a method of treating a subject by administering the formulation in the recited dosage amount. Therefore, merely changing the concentration of the enzyme in a formulation would not be expected to have any effect on the ability of the administered composition to treat the subject because the subject is still being administered “0.05 mg/kg to 1 mg/kg”. This position is supported by Georgiou’s disclosure that the practitioner responsible for administration will, in any event, determine the concentration of active ingredients in a composition and appropriate doses for the individual subject ([0197]).
Thus, claims 5-6 are obvious over Georgiou as a result of routine experimentation.
Regarding claim 7, Georgiou teaches that the composition may be administered intravenously or subcutaneously ([0021], [0134]-[0135], and [0191]).
Regarding claim 8, Georgiou teaches that the composition may be administered weekly (i.e., one dose per week)([0199]).
Regarding claim 9, as discussed above, Georgiou makes obvious the method of claim 1. Although Georgiou does not teach the dosing regimen of intravenous administration for four weeks, followed by subcutaneous administration in subsequent weeks, as discussed above, a person having ordinary skill in the art could have arrived at this dosing regimen through routine experimentation. Georgiou teaches that the CGL enzyme can be administered through repeated dosing ([0130]) and gives specific working examples wherein mice were administered modified CGL every 5 days for 30 days ([0205]). Additionally, Georgiou teaches that the quantity to be administered depends on the subject to be treated, capacity of the subject’s system to utilize the active ingredient and degree of therapeutic effect desired ([0137]). Georgiou teaches that multiple administrations are preferred in order to maintain continuously high serum and tissue levels of modified CGL enzyme and conversely low serum and tissue levels of homocyst(e)ine. Accordingly, a person having ordinary skill in the art would have been prompted to perform this experimentation in order to achieve treatment of homocystinuria or hyperhomocysteinemia. There is no evidence of record that intravenous administration for four weeks, followed by subcutaneous administration in subsequent weeks elicits an unexpected or remarkable result.
Thus, claim 9 is obvious over Georgiou as a result of routine experimentation.
Regarding claims 10-12, as discussed above, Georgiou makes obvious the method of claim 1. Georgiou teaches that the dose may comprise from about 500 micrograms/kg (i.e., 0.5 mg/kg) to about 750 mg/kg body weight ([0199]). This range disclosed by Georgiou overlaps with the recited ranges of about “about 0.1 mg/kg to about 1 mg/kg” (claim 10), “about 0.1 mg/kg to about 1 mg/kg” (claim 11), and “about 1 mg/kg” (claim 12). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (MPEP § 2144.05(I)).
And although some claims recite values falling outside of Gerogiou’s teachings, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close (MPEP § 2144.05(I)). In this case, values such as 0.1 mg/kg or 0.15 mg/kg are considered to be “close” to “about 1 mg/kg”.
Thus, claims 10-12 are obvious over Georgiou.
Regarding claim 13, Georgiou teaches that therapeutic compositions are typically prepared as liquid solutions or suspensions for use as injectables and are combined with diluents such as saline ([0188] and [0193]). Accordingly, it would have been obvious for the formulation to be diluted in saline prior to intravenously administering to the subject.
Regarding claim 14, Georgiou teaches that the subject is a human patient ([0008]).
Regarding claim 17, Georgiou teaches that classical homocystinuria treatments include methionine-restricted diets as well as high doses of vitamin B6 and betaine ([0006]). Additionally, Georgiou teaches that the subject or patient may be maintained on such a diet or on a normal diet ([0008]). Accordingly, Georgiou teaches the method wherein the patient is on an individualized diet. Applicant has not provided a special definition for the term “individualized diet”, which is interpreted to be any diet tailored to the patient’s condition which is not a normal diet (e.g., the methionine-restricted diet).
Regarding claim 18, Georgiou teaches that the subject is maintained on a methionine-restricted diet ([0008]).
Regarding claim 19, Georgiou teaches that the dosage ranges for the administration of therapeutic compositions are those large enough to produce the desired effect in which the symptoms of homocystinuria are reduced ([0107]). This includes a reduction in the symptoms of a disease such as elevated serum level of total homocysteine (Id.).
As such, the method reduces total plasma homocysteine levels.
Regarding claims 20-22, Georgiou teaches that patients with homocystinuria also suffer from hyperhomocysteinemia in which the serum homocysteine (Hcy) exceeds 15 µM ([0005]) and teaches that the method may reduce the Hcy to less than 25 µM ([0007]). Additionally, Georgiou teaches reducing symptoms of the disease such as elevated serum levels of total homocysteine to below 15 µM ([0107]). Finally, Georgiou teaches that the administered dosage could result in tHcy reduced to a level less than 20-25 µM.
As such, Georgiou provides a litany over Hcy concentrations which overlap with “less than or equal to about 80 µM”, “less than or equal to about 50 µM”, and “less than or equal to about 15 µM”. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (MPEP § 2144.05(I)). Additionally, it is noted that it would be particularly advantageous to reduce the levels to a value such as less than 15 µM because, as discussed above, Georgiou teaches that this is the point at which a patient is considered to have hyperhomocysteinemia and the method is for treatment of hyperhomocysteinemia ([0004]).
Claims 1-15 and 17-22 are rejected under 35 U.S.C. 103 as being unpatentable over Georgiou et al. (US 2018/0326025 A1; cited in IDS filed on 12/18/2023) and Maron et al. (Annual Review of Medicine, 2009, Vol. 60, pages 39-54).
The teachings of Georgiou are set forth above and applied herein. Georgiou is found to render obvious claims 1-14 and 17-22.
Regarding claim 15, as discussed above, Georgiou renders obvious the method of claim 1.
The methods of Georgiou differ because although it teaches the administration to homocystinuria and hyperhomocysteinemia patients ([0007]) it does not teach that the subject has a total plasma homocysteine level greater than 80 µM prior to initiating therapy with administering the formulation.
Maron et al. (hereinafter Maron) teaches that according to the American Heart Association, the normal homocysteine concentrations range from 5-15 µmol/L (although 12 µmol/L is regarded as elevated by others), intermediately elevated levels are between 31-100 µmol/L and severely elevated levels are > 100 µmol/L, which is essentially pathognomonic for the presence of an inborn error of homocysteine metabolism causing homocystinuria (p. 2, par. 4).
Thus, because Georgiou is directed to treating patients having homocystinuria and hyperhomocysteinemia and because Maron teaches that elevated levels range from 31-100 µM and severely elevated levels are > 100 µM, it would have been obvious to have treated a subject which has a total plasma homocysteine level greater than 80 µM prior to initiating therapy with administering the formulation. There would have been a reasonable expectation of success because Georgiou teaches that the method addresses the need of all patients by reducing blood homocysteine levels back to the normal range ([0006]; emphasis added) and because the patient population taught by Georgiou (i.e., those having homocystinuria) would be expected to have elevated or severely elevated homocysteine levels. This obviousness is based upon the “Some Teachings, Suggestion, or Motivation in the Prior Art That Would Have Led One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior Art Reference Teachings To Arrive at the Claimed Invention” rationale set forth in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007). See MPEP 2143(I)(G).
Thus, claim 15 is obvious over Georgiou in view of Maron.
Claims 1-14 and 17-22 are rejected under 35 U.S.C. 103 as being unpatentable over Georgiou et al. (US 2018/0326025 A1; cited in IDS filed on 12/18/2023) and Jacques et al. (American Journal of Clinical Nutrition, 1999, Vol. 69, pages 482-489).
The teachings of Georgiou are set forth above and applied herein. Georgiou is found to render obvious claims 1-14 and 17-22.
Regarding claim 16, as discussed above, Georgiou renders obvious the method of claim 1.
The teachings of Georgiou differ from the instant claim because Georgiou does not specifically teach administration to a subject wherein the subject is at least 12 years of age.
Nonetheless, it was previously known that age and sex are two of the strong determinants of fasting homocysteine (Jacques, p. 482, right col., par. 2). Specifically, Jacques studied homocysteine concentrations in males and females which are at least 12 years of age (see, e.g., p. 484, Table 1). Jacques concludes that “homocysteine concentrations increased rapidly in males across age groups” (p. 484, left col., par. 2).
Thus, although Georgiou only teaches the method in a human, it would have been obvious to have used the method in a human in the broad range of “at least 12 years of age” because it was known that homocysteine is present in humans “at least 12 years of age” and because it was also known that homocysteine concentrations are positively correlated with age. Additionally, there would have been a reasonable expectation of success because the method merely relies on treating a subject having or at risk of developing homocystinuria or hyperhomocysteinemia and this method would be expected to work on any age group as the mechanism is not directed to the age of the patient. This obviousness is based upon the “Some Teachings, Suggestion, or Motivation in the Prior Art That Would Have Led One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior Art Reference Teachings To Arrive at the Claimed Invention” rationale set forth in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007). See MPEP 2143(I)(G).
Thus, claim 16 is obvious over Georgiou in view of Jacques.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Previous double patenting rejections
RE: Rejection of claims 1-3 on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 11,033,612 B2.
Applicant traverses by arguing that ‘612 does not teach or suggest any dosage level and a skilled artisan would not have had any reasonable expectation of success in using an enzyme dose at the extreme low end of the disclosed range and even lower beyond that. Applicant supports this argument by stating that dosing CBS KO mice with the enzyme subcutaneously at 1.0 mg/kg, 3.0 mg/kg, or 10.0 mg/kg significantly increased survival when compared to vehicle.
Applicant’s arguments have been fully considered but are not sufficient to overcome the rejection of record.
‘612 teaches an identical method of treating a subject having or at risk of developing homocystinuria or hyperhomocysteinemia (claim 26) by administering an identical enzyme (mutant 3; hCGL-E59I-S63L-L91M-R119D-K268R-T311G-E339V-I353S). And although the claims of ‘612 do not teach administering the particular amount recited in applicant’s claims (“0.05 mg/kg to 1 mg/kg at a frequency of one dose per day to one dose per month”), a person having ordinary skill in the art could have routinely experimented in order to determine the optimal dosing strategy. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical (MPEP § 2144.05(II)(A)). In rebutting a case of prima facie obviousness to routinely experiment with concentrations, applicant should show that the range is critical, show that the prior art teaches away from the claimed range, show that the claimed range was not recognized as result-effective, or show that the claimed range is disclosed in a very broad range (MPEP § 2144.05(III)(A-D)). In this case, the optimization clearly does not result in a critical range as evidenced by applicant’s admission that “[t]here was no observed correlation between the dose level and percent survival as all dose levels resulted in ≥ 80% survival” (Remarks, p. 9, par. 1). Similarly, the claimed range was clearly considered to be “results-effective” as evidenced by the definition of “therapeutically effective amount” provided in ‘612, which states that the therapeutically effective amount is “anything that promotes or enhances the well-being of the subject with respect to the medical treatment of this condition” (col. 13, lines 57-67). Thus, any amount would be expected to be results-effective. There is no evidence demonstrating that the art teaches away from the claimed range and although the examiner agrees that ‘612’s range is broad, there is no argument presented that the disclosure is so broad in light of the dissimilar characteristics as to not invite optimization (MPEP § 2144.05(III)(A)). To the contrary, as discussed above, applicant admits that the actual administered amount is largely irrelevant because it does not alter survival and ‘612 teaches that a suitable amount is any amount which promotes or enhances the well-being of the subject.
Thus, performing ‘612’s methods with ‘612’s composition is not non-obvious merely because the administered range is not taught in ‘612’s claims.
For at least this reason, the rejection of record must be maintained. In order to address the newly examined claims, the rejection is withdrawn and a new ground of rejection is set forth below.
New ground of rejection for double patenting
Claims 1-8, 10-12, 14, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 11,033,612 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Regarding claim 1, the instant claim is directed to methods of treating a subject having or at risk of developing homocystinuria or hyperhomocysteinemia comprising administering a therapeutically effective amount of formulation comprising a modified hCGL enzyme. Claim 24 of ‘612 recites a method of treating a subject having or at risk of developing homocystinuria or hyperhomocysteinemia comprising administering to the subject a therapeutically effective amount of the formulation of claim 6. Claim 6 of ‘612 recites a therapeutic formulation comprising the isolated, modified hCGL enzyme of claim 1 and a pharmaceutically acceptable carrier. The instant claim further requires at least the following substitutions relative to a native hCGL enzyme: 59I, 63L, 91M, 119D, 268R, 311G, 339V, and 353S. Claim 1 of ‘612 recites 59I, 63L, 91M, 119D, 268R, 311G, 339V, and 353S. Accordingly, the claims of ‘612 are directed to the same subject matter.
The claims differ in that they do not recite the enzyme dose and dosage frequency as seen in lines 9-10 of claim 1. Nevertheless, a person having ordinary skill in the art could have arrived at this dosing regimen as a result of routine experimentation. A person having ordinary skill in the art would have readily recognized that various amounts and doses of the therapeutic composition could be administered and there would have been a reasonable expectation of success because the modification would merely be expected to change the efficacy of ‘612’s methods.
Regarding claim 2, claim 26 of ‘612 teaches the method wherein the enzyme is coupled (i.e., bound) to at least one (i.e., one or more) PEG.
Regarding claim 3, as discussed above, claim 6 of ‘612 teaches the inclusion of a pharmaceutically acceptable carrier.
Regarding claim 4, as discussed above, claim 24 of ‘612 teaches the method. And although the claims are silent as to the formulation being 2 mL of a liquid supplied in a 5 mL vial, a person having ordinary skill in the art could have arrived at this formulation through routine experimentation. There is no evidence that placing ‘612’s composition in 2 mL of a liquid in a 5 mL vial affects ‘612’s methods in any way, let alone to a non-obvious extent. The claim is to a method of administering a composition in a given dosage range and therefore (based upon the record), the amount of liquid or the container in which it is stored is largely irrelevant to the method.
Regarding claims 5-6, these claims merely limit the concentration of the enzyme. As discussed above, it would have been obvious to have arrived at the dose by routine experimentation. Similarly, the concentration of the composition used in the dose would be a result of routine experimentation. There is no evidence that the range is critical.
Regarding claim 7, ‘612 teaches intravenous administration (claim 27).
Regarding claim 8, as discussed above, claim 24 of ‘612 teaches the method. A person having ordinary skill in the art could have arrived at a method of administering one dose per week by routine optimization of ‘612’s methods. Similarly, it would have been obvious to have modified the method such that it is administered more than once. A person having ordinary skill in the art would expect that administering the composition more than once (such as by one dose per week) would improve the method by providing more of the active composition to the subject in need of treatment.
Regarding claims 10-12, as discussed above, claim 24 of ‘612 teaches the method. The claims differ because they recite a range of administered dose. Nevertheless, a person having ordinary skill in the art could have arrived at this dosing regimen as a result of routine experimentation. A person having ordinary skill in the art would have readily recognized that various amounts and doses of the therapeutic composition could be administered and there would have been a reasonable expectation of success because the modification would merely be expected to change the efficacy of ‘612’s methods.
Regarding claim 14, ‘612 defines a “subject” as being a human or non-human subject and teaches that “subject” is interchangeable with “patient” (col. 14, lines 59-61). As such, ‘612 is directed to treatment of a human patient.
Regarding claim 19, ‘612 defines a “therapeutically effective amount” (the amount used in the claims of ‘612) as meaning an amount which depletes homocysteine in a patient’s circulation that is at or below a normal reference value (col. 13, lines 57-67). As such, ‘612’s methods reduce total plasma homocysteine levels.
Claims 1-14, and 17-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 11,033,612 B2 in view of Georgiou et al. (US 2018/0326025 A1; cited in IDS filed on 12/18/2023).
For the reasons discussed above, claims 1-8, 10-12, 14, and 19 are unpatentable over ‘612.
Regarding claim 9, as discussed above, ‘612 makes obvious the method of claim 1. Although ‘612 does not teach the dosing regimen of intravenous administration for four weeks, followed by subcutaneous administration in subsequent weeks, as discussed above, a person having ordinary skill in the art could have arrived at this dosing regimen through routine experimentation. Georgiou teaches that the CGL enzyme can be administered through repeated dosing ([0130]) and gives specific working examples wherein mice were administered modified CGL every 5 days for 30 days ([0205]). Georgiou teaches subcutaneous and intravenous administration ([0191]). Additionally, Georgiou teaches that the quantity to be administered depends on the subject to be treated, capacity of the subject’s system to utilize the active ingredient and degree of therapeutic effect desired ([0137]). Georgiou teaches that multiple administrations are preferred in order to maintain continuously high serum and tissue levels of modified CGL enzyme and conversely low serum and tissue levels of homocyst(e)ine. Accordingly, a person having ordinary skill in the art would have been prompted to perform this experimentation in order to achieve treatment of homocystinuria or hyperhomocysteinemia. There is no evidence of record that intravenous administration for four weeks, followed by subcutaneous administration in subsequent weeks elicits an unexpected or remarkable result.
Thus, claim 9 is obvious over Georgiou as a result of routine experimentation.
Regarding claim 13, although ‘612 does not teach that the therapeutic composition is diluted in saline, Georgiou teaches that therapeutic compositions are typically prepared as liquid solutions or suspensions for use as injectables and are combined with diluents such as saline ([0188] and [0193]). Accordingly, it would have been obvious for the formulation to be diluted in saline prior to intravenously administering to the subject.
Regarding claims 17-18, although ‘612 doesn’t define the diets of the subjects, Georgiou is the pre-grant publication of ‘612 and teaches that classical homocystinuria treatments include methionine-restricted diets as well as high doses of vitamin B6 and betaine ([0006]). Additionally, Georgiou teaches that the subject or patient may be maintained on such a diet or on a normal diet ([0008]). Accordingly, Georgiou teaches the method wherein the patient is on an individualized diet. Applicant has not provided a special definition for the term “individualized diet”, which is interpreted to be any diet tailored to the patient’s condition which is not a normal diet (e.g., the methionine-restricted diet). Additionally, Georgiou teaches that the subject is maintained on a methionine-restricted diet ([0008]).
Regarding claims 20-22, as discussed above, ‘612 defines the treatment regimen as reducing the level of serum homocysteine to normal levels. And although ‘612 doesn’t teach specific levels of total plasma homocysteine, Georgiou teaches that patients with homocystinuria also suffer from hyperhomocysteinemia in which the serum homocysteine (Hcy) exceeds 15 µM ([0005]) and teaches that the method may reduce the Hcy to less than 25 µM ([0007]). Additionally, Georgiou teaches reducing symptoms of the disease such as elevated serum levels of total homocysteine to below 15 µM ([0107]). Finally, Georgiou teaches that the administered dosage could result in tHcy reduced to a level less than 20-25 µM.
As such, Georgiou provides a litany over Hcy concentrations which overlap with “less than or equal to about 80 µM”, “less than or equal to about 50 µM”, and “less than or equal to about 15 µM”. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (MPEP § 2144.05(I)). Additionally, it is noted that it would be particularly advantageous to reduce the levels to a value such as less than 15 µM because, as discussed above, Georgiou teaches that this is the point at which a patient is considered to have hyperhomocysteinemia and the method is for treatment of hyperhomocysteinemia ([0004]).
Claims 1-15 and 17-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 11,033,612 B2 in view of Maron et al. (Annual Review of Medicine, 2009, Vol. 60, pages 39-54).
For the reasons discussed above, claims 1-8, 10-12, 14, and 19 are unpatentable over ‘612.
Regarding claim 15, although ‘612 teaches treating a subject having homocystinuria or hyperhomocysteinemia, it does not specifically teach that the subject has a total plasma homocysteine level greater than 80 µM.
Maron teaches that according to the American Heart Association, the normal homocysteine concentrations range from 5-15 µmol/L (although 12 µmol/L is regarded as elevated by others), intermediately elevated levels are between 31-100 µmol/L and severely elevated levels are > 100 µmol/L, which is essentially pathognomonic for the presence of an inborn error of homocysteine metabolism causing homocystinuria (p. 2, par. 4).
Thus, because ‘612 is directed to treating patients having homocystinuria and hyperhomocysteinemia and because Maron teaches that elevated levels range from 31-100 µM and severely elevated levels are > 100 µM, it would have been obvious to have treated a subject which has a total plasma homocysteine level greater than 80 µM prior to initiating therapy with administering the formulation.
Claims 1-14 and 16-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 11,033,612 B2 in view of Jacques et al. (American Journal of Clinical Nutrition, 1999, Vol. 69, pages 482-489).
For the reasons discussed above, claims 1-8, 10-12, 14, and 19 are unpatentable over ‘612.
Regarding claim 16, the teachings of ‘612 differ from the instant claim because ‘612 does not specifically teach administration to a subject wherein the subject is at least 12 years of age.
Nonetheless, it was previously known that age and sex are two of the strong determinants of fasting homocysteine (Jacques, p. 482, right col., par. 2). Specifically, Jacques studied homocysteine concentrations in males and females which are at least 12 years of age (see, e.g., p. 484, Table 1). Jacques concludes that “homocysteine concentrations increased rapidly in males across age groups” (p. 484, left col., par. 2).
Thus, although ‘612 only teaches the method in a human, it would have been obvious to have used the method in a human in the broad range of “at least 12 years of age” because it was known that homocysteine is present in humans “at least 12 years of age” and because it was also known that homocysteine concentrations are positively correlated with age.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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