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 .
Claim 73 has been added.
Claims 1-5, 20-32, 36-46, and 72-73 are pending.
Claims 6-19, 33-35, and 47-71 are cancelled.
Claims 20-32 and 36-46 are withdrawn.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/08/2026 has been entered.
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.
Claims 1, 2, 4, 5 and 73 are rejected under 35 U.S.C. 103 as obvious over CELLIS (WO 2016/207257 A1) in view of BANJERJEE (Faster heme loss from hemoglobin E than HbS, in acidic pH: Effect of aminophospholipids. Journal of Bioscience. 2011.) and REIS (Protein Ultrafilteration. Encyclopedia of Industrial Biotechnology: Bioprocess, Bioseparation, and Cell Technology. 2010.).
With respect to claim 1 and 5, CELLIS teaches pharmaceutical composition comprising various iron binding complexes, such as a hemoglobin-haptoglobin complex (claim 10). The iron binding complex are beneficial due to the ability to encapsulate drugs (Page 34, paragraph 2). CELLIS further teaches that apo-hemoglobin, hemoglobin that has the heme removed, is beneficial for use in drug delivery due to its capability of hosting several hydrophobic molecules within the empty heme pocket (Page 20, paragraph 3). The heme can be displaced by the pocket and be replaced by drugs linked to the complex by proteins (page 35, paragraph 2), such as transferrin (Page 19, paragraph 3).
CELLIS does not have an example that has the apohemoglobin with haptoglobin.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate swapping hemoglobin for apo-hemoglobin in the hemoglobin-haptoglobin complex. The person of ordinary skill in the art would have been motivated to make those modifications, because apo-hemoglobin, hemoglobin that has the heme removed, is beneficial for use in drug delivery due to its capability of hosting several hydrophobic molecules within the empty heme pocket, and reasonably would have expected success because both hemoglobin and apo-hemoglobin re taught in the reference and the purpose of the composition is to encapsulate and deliver drugs.
BANERJEE teaches that it is common in the art to measure the loss of heme from hemoglobin at an absorption of 415 nm, also called the Soret peak (page 811, paragraph 4). The wavelengths of maximum absorption for various hemoglobins going through heme loss (page 810, paragraph 1), at a pH of 4 one of the hemoglobins has a maximum absorption of roughly 412 (figure 1).
REIS teaches that ultrafiltration is commonly used to purify proteins (introduction) and can be optimized using various its various aspects to achieve the desired purification factor (page 18, paragraph 1).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate an absorption of 415 nm. The person of ordinary skill in the art would have been motivated to make those modifications, because it is common to measure the loss of heme from hemoglobin (which would create apohemoglobin) at a Soret peak of 412 nm, and reasonably would have expected success because the references are in the same field of endeavor such as apohemoglobin.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using an ultrafiltration method to purify the apohemoglobin. The person of ordinary skill in the art would have been motivated to make those modifications it can be optimized to achieve the desired level of purification and reasonably would have expected success because it is a common method used in the art to purify proteins.
CELLIS does not specifically teach the weight ratio of apohemoglobin-haptoglobin as claimed by the Applicant. The weight ratio is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal weight ratio in order to best achieve desired results, such as the desired amount of drug binding. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the weight ratio would have been obvious at the time of Applicant’s invention.
Regarding claim 73, since the same composition is taught by the prior art, it would have the same properties, such as enhanced stability.
Claims 1-5 and 72-73 are rejected under 35 U.S.C. 103 as being unpatentable over CELLIS (WO 2016/207257 A1), BANJERJEE (Faster heme loss from hemoglobin E than HbS, in acidic pH: Effect of aminophospholipids. Journal of Bioscience. 2011.) and REIS (Protein Ultrafilteration. Encyclopedia of Industrial Biotechnology: Bioprocess, Bioseparation, and Cell Technology. 2010.) in view of DALTON (US 2009/0281282 A1). CELLIS, BANJERJEE and REIS teach Applicant’s invention above.
CELLIS, BANJERJEE and REIS do not teach the molecular weight of haptoglobin.
DALTON teaches a haptoglobin pharmaceutical composition. DALTON teaches that haptoglobin has various phenotypes that can be used in pharmaceutical compositions (Page 1, paragraph 0005). One phenotype, Hp 1-1 has a molecule weight of 100 kDa or 165 kDa when complexed with hemoglobin (Page 1, paragraph 0005). DALTON only mentions the Hp 1-1 is complexed with hemoglobin (Page 1, paragraph 0005). It is also noted that the average molecular weight of haptoglobin ranges from 4—950 kDa.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate the molecular weight of haptoglobin. The person of ordinary skill in the art would have been motivated to make those modifications, because the phenotypes are readily available and can be chosen for the particular composition being created, and reasonably would have expected success because the references are in the same field of endeavor, such as hemoglobin- haptoglobin complexes.
Response to Arguments
Applicant argues CELLIS teaches that "[a]po-haemoglobin thus obtained is capable of hosting several hydrophobic molecules within the empty heme pocket." CELLIS, page 20, lines 21-26. This description relates to the use of apohemoglobin alone for drug delivery purposes, not to an apohemoglobin-haptoglobin complex as recited by claim 1. CELLIS discusses hemoglobinhaptoglobin complexes and apohemoglobin as separate entities for different purposes. Applicants respectfully submit that the Office's assertion that "all that is needed is swapping hemoglobin for apo-hemoglobin" represents impermissible hindsight reconstruction. CELLIS provides no teaching, suggestion, or motivation to combine apohemoglobin with haptoglobin to form a complex.
Examiner does not find the argument persuasive because as discussed above, it would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate swapping hemoglobin for apo-hemoglobin in the hemoglobin-haptoglobin complex. The person of ordinary skill in the art would have been motivated to make those modifications, because apo-hemoglobin, hemoglobin that has the heme removed, is beneficial for use in drug delivery due to its capability of hosting several hydrophobic molecules within the empty heme pocket, and reasonably would have expected success because both hemoglobin and apo-hemoglobin re taught in the reference and the purpose of the composition is to encapsulate and deliver drugs.
Applicant argues BANERJEE teaches monitoring "the absorption of heme at 415 nm to study the loss of heme from hemoglobin at pH 3.0" where "the Soret peak at 415 nm showed an abrupt blue shift to 380 nm at and below pH 3.0." BANERJEE, Section 3.1. This teaching relates to measuring heme loss during acidic conditions, not to characterizing apohemoglobin in a pharmaceutical composition. Claim 1 recites "wherein the apohemoglobin is characterized by a residual Soret peak having a maximum absorption at 411-417 nm." As described in the specification, apoHb produced by the claimed methodology "can be characterized by a residual Soret peak having a maximum absorption ranging from 411-417 nm, such as 412 nm ( after renaturation/neutralization, but before complexation with Hp). Previous methodologies produced apoHb which had a residual Soret peak at 402-407 nm." As-Filed Specification, page 22, lines 10-12. This distinguishes the claimed apohemoglobin from that discussed in BANERJEE, which relates to heme loss under acidic conditions rather than properly prepared apohemoglobin for pharmaceutical use.
Examiner does not find the argument persuasive because BANERJEE is cited to show that it is common in the art to measure the loss of heme from hemoglobin at an absorption of 415 nm, also called the Soret peak (page 811, paragraph 4). The wavelengths of maximum absorption for various hemoglobins going through heme loss (page 810, paragraph 1), at a pH of 4 one of the hemoglobins has a maximum absorption of roughly 412 (figure 1). The measurements simply show that apo hemoglobin has a Soret peak at the claimed range.
Applicant argues DALTON describes that "[t]he core function of Hp is as a haemoglobin (Hb) binding protein, required for terminal processing and disposal of free Hb." DALTON, paragraph [0002]. DALTON further describes that "Hp 1-1 has a molecular mass of 100 kDa, or 165 kDa when complexed with Hb." DALTON, paragraph [0005]. These descriptions relate to haptoglobin's function in binding hemoglobin, not apohemoglobin. DALTON identifies haptoglobin "as a potential treatment for renal disorders caused by haemolysis" and discusses its use "as a means of removing free haemoglobin." DALTON, paragraph [0006]. DALTON does not disclose or suggest complexing haptoglobin with apohemoglobin. Accordingly, neither CELLIS nor DALTON, alone or in combination, disclose or suggest "a pharmaceutical composition comprising an apohemoglobin-haptoglobin complex, wherein the apohemoglobin is characterized by a residual Soret peak having a maximum absorption at 411-417 nm" as recited by claim 1.
Examiner does not find the argument persuasive because DALTON is not cited for its combination with apo hemoglobin, but rather the molecular weight of haptoglobin. It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate the molecular weight of haptoglobin. The person of ordinary skill in the art would have been motivated to make those modifications, because the phenotypes are readily available and can be chosen for the particular composition being created, and reasonably would have expected success because the references are in the same field of endeavor, such as hemoglobin- haptoglobin complexes.
Conclusion
No claims are allowable.
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/S.L.M./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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