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 .
Status of Claims
Claims 1-13 are currently pending and under consideration.
Priority
The present application is a continuation of U.S. application 17/016,849, now U.S. Patent 11662353, filed on 09/10/2020. The present application and all claims are being examined with an effective filing date of 09/10/2020. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/25/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
In paragraph 0003, on page 1, “oixygen” should be amended to “oxygen”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
It is noted that MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow. Claim 1 has been broadly interpreted as encompassing a genus of methods for assessing an effect of hypoxia on a genus of tissues, comprising, inter alia, providing a first sample of tissue in a first hermetically sealed container, determining a first amount of a genus of reaction substrates to be introduced into said container, and determining a second amount of a genus of reaction enzymes into said container.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) states that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
In the instant case, the claims are broadly drawn to a method of assessing the effect of hypoxia comprising the use of a genus of substrates and enzymes for assessing hypoxia on a tissue. The specification limits the methods of enzymatic catalysis of oxygen in liquids to three known systems; glucose oxidase/catalase system (GOC), Pyranose Oxidase/Catalase, and PCA/PCD.
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Despite the variety of enzyme systems above, the specification only appears to be in possession of the reliable enzyme/substrate pair: protocatechuic acid and protocatechuate dioxygenase because other “methods have not been suitable for use in assessing tissues and changes in tissues under the differences in hypoxic conditions occurring throughout the human body due to normal physiology, conditions, or pathologies. Significantly, these methods have not been suitable for assessing tissues and changes in tissues occurring at different rates of increasing hypoxia (or tissue deoxygenation) and decreasing hypoxia (on tissue reoxygenation) levels” (para 0025). For example, the specification appears to disclose that the enzymes glucose oxidase and pyranose oxidase cannot be used alone, as claimed, and must be used in conjunction with catalase because the reaction they catalyze produces reactive oxygen species (para 0024). The specification does not provide guidance on determining other possible enzymes and substrates that would or would not be acceptable for use in the claimed method beyond providing broad goals for the invention, and does not provide any examples of acceptable enzymes/substrates other than protocatechuate dioxygenase and protocatechuic acid (PCA/PCD).
One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus. Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the claimed invention.
Claim Rejections - 35 USC § 112(b)
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite due to the recitation of “a predetermined amount of hypoxia less than anoxia.” It is unclear what degree or level of oxygen deprivation constitutes “less than anoxia,” since “anoxia” refers to the complete absence of oxygen. How can there be less than zero oxygen? The phrase “less than anoxia” is therefore internally inconsistent and fails to provide a clear boundary for the scope of the claimed limitation. One of ordinary skill in the art would not be reasonably apprised of the conditions encompassed by this language.
Claim 1 is further indefinite and unclear due to the recitation of “a predetermined rate of hypoxia”, because the claim does not specify how the rate is determined, what parameters define hypoxia rate, or what range of rates would be acceptable. Without an objective standard for measuring or comparing such a rate, the metes and bounds of the claim cannot be determined with reasonable certainty. For the purpose of compact prosecution, the term anoxia is being interpreted consistent with the instant specification (see para 0003), as referring to conditions with “extremely low or no oxygen”, corresponding to “less than 5% of normoxic partial oxygen pressure”. Therefore, “a predetermined amount of hypoxia less than anoxia” is interpreted as an oxygen level between 1-5%.
Additionally, claim 1 recites steps of “determining a first amount of a reaction substrate”, “determining a second amount of a reaction enzyme” and “selecting…to induce a predetermined amount” or “rate of hypoxia…”. It is unclear whether the recited “determining” and “selecting” steps require a tangible operation (e.g., measuring, computing, etc.) or instead represent a purely mental act/step of deciding or determining quantities in the mind of the practitioner. Likewise, the term “predetermined” implies that the claimed method involves prior mental consideration or intention. For examination purposes, these “determining” and “selecting” steps are interpreted as non-tangible mental acts that do not contribute additional operational limitations to the claimed method – wherein the only active process step is therefore interpreted as that involving the physical introduction of the reaction substrate and reaction enzyme into the hermetically sealed container.
Claims 8 and 11 are indefinite due to the recitation of “a predetermined rate of reoxygenation”, as it is unclear how such a rate is determined, what parameters define reoxygenation rate, or what range of rates would be acceptable. Without an objective standard for measuring or comparing the rate, the metes and bounds of the claims cannot be determined with reasonable certainty. Additionally, the term “predetermined” implies that the rate is defined in advance through prior mental consideration rather than by any objective measurable parameter. The claim does not specify how such a ”predetermined” rate is achieved, leaving it unclear whether this limitation imposes a tangible step or merely reflects an intended result. For examination purposes, “predetermined rate of reoxygenation” will be interpreted as referring to an intended or targeted rate established by the practitioner through a mental step.
Claim 8 is further indefinite due to the recitation of “introducing, after the reaction is complete, oxygen to the sample, with at least one of the first amount of the reaction substrate and the second amount of the reaction enzyme selected to induce a predetermined rate of reoxygenation of the tissue upon introduction of the oxygen”. It is unclear how the amount of reaction substrate and reaction enzyme (which function as oxygen scavenging components according to claim 1) could be selected to induce a rate of reoxygenation – a process that occurs only after oxygen is externally introduced. The recited substrate and enzyme catalyze oxygen consumption (i.e., inducing hypoxia) not oxygen reintroduction. Therefore, it is further unclear what structural or process parameter determines the claimed “predetermined rate of reoxygenation”. The scope of this claim cannot be determined with reasonable certainty. For examination purposes, the claim is interpreted as comprising the step of introducing oxygen to the sample, after introduction of the reaction substrate and reaction enzyme according to claim 1.
Claim 9 recites the limitation "a first value of the property" in line 6. However, it is unclear as to what “property” is being referred to, as no such property is introduced or defined in the claim(s) prior to this limitation. There is insufficient antecedent basis for this limitation in the claim, rendering the claim indefinite.
Claim 9 is indefinite due to recitation of “a first value of the property”…“a second value of a property”…”and, determining the change in the value of the property responsive to the first and second values of the property”. It is unclear whether the “second value of a property” refers to the same property recited in “a first value of the property”, or to a different property altogether. Further, it is unclear which property the “change in value” pertains to, or what is meant by “responsive to the first and second values of the property”. If the first and second values are intended to represent measurements of the same property under different conditions, then the “change in value” would simply represent the difference between those measurements. However, the phrase “responsive to the first and second values” suggests an additional causal or functional relationship that is undefined and scientifically unclear. Accordingly, the scope of claim 9 cannot be determined with reasonable certainty.
Claim 11 is indefinite and unclear due to the recitation of “with at least one of the first amount of the reaction substrate and the second amount of the reaction enzyme selected to induce a predetermined rate of reoxygenation…”. As described above (for claim 8), it is unclear how the amount of reaction substrate and reaction enzyme (which function as oxygen scavenging components according to claim 1) could be selected to induce a rate of reoxygenation – a process that occurs only after oxygen is externally introduced. The recited substrate and enzyme catalyze oxygen consumption (i.e., inducing hypoxia) not oxygen reintroduction. Therefore, it is further unclear what structural or process parameter determines the claimed “predetermined rate of reoxygenation”. The scope of this claim cannot be determined with reasonable certainty. Additionally, it is unclear what property (in claim 9) is being referenced, as claim 11 depends on claim 9, and recites “measuring, after reoxygenation of the third sample of the tissue to the initial oxygenation level, a third value of the property of the tissue”.
Claim 11 is also indefinite due to the recitation of “determining a third amount of a reaction substrate” and “determining a fourth amount of a reaction enzyme”. The same reasoning described above for the recitation of “determining” in claim 1 applies. It is unclear whether these “determining” steps require a tangible operation (e.g., measuring, computing, etc.) or instead represent a purely mental act/step of deciding or determining quantities in the mind of the practitioner. For examination purposes, these steps are interpreted as non-tangible mental acts that do not contribute additional operational limitations to the claimed method.
Regarding claims 9 and 11, and the recitations of “the property” and “a property” for the different samples –for examination purposes, the examiner is interpretating the claims as essentially reciting a three-condition experimental design (i.e., sample 1-hypoxic/deoxygenated and sample 2-normoxic, in claim 9; and sample 3-deoxygenated then reoxygenated, in claim 11) that measures the same property across all three.
Claim 11 is further indefinite due to the recitation of “after reoxygenation”, as it is unclear what level of reoxygenation would be acceptable. The specification simple states that a sample can be reoxygenated to a desired amount (para 0059-0060), but fails to describe how one would determine the desired amount. Accordingly, it is unclear whether any increase in oxygen levels would be sufficient to meet the claim language, whether there is a minimum increase required, or a specific increase that is required (and how to determine that amount). For examination purposes, the examiner is interpreting “after reoxygenation” as encompassing any increase in oxygen level.
Claims 10 and 12 are indefinite and unclear due to the recitation of “measuring a change in mechanical fragility” of the tissue or sample. The term “mechanical fragility” is not defined in the specification and does not have a generally accepted meaning in the art with respect to any and all tissue samples. While para 0045 of the instant specification describes that “measurement of mechanical fragility may be obtained, for example, by agitating the sample through, for example, alternate application of electromagnets… followed by directing electromagnetic radiation (e.g., light) through the sample and conducting a spectral analysis of the sample”, and further notes that “mechanical fragility of red blood cells has previously been used to evaluate the potential of irreversible or poorly reversible membrane modification”, this disclosure fails to establish with reasonable clarity the specific characteristics being measured or the parameters that would constitute a change in mechanical fragility for general “tissue”. Thus, the term is subject to multiple plausible interpretations – e.g., shear-induced hemolysis in red blood cells, elasticity of cell membranes, etc. For the purpose of compact prosecution, the term “mechanical fragility” is being interpreted as referring to the susceptibility of erythrocyte membranes to rupture under applied mechanical stress. However, appropriate clarification and response is required.
Clarification and response to all of the above is required.
Claims 2-7 have been included in this rejection because they depend from one or more base claims found to be indefinite and do not add limitations that clarify the noted ambiguities or otherwise resolve the uncertainty regarding claim scope.
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, 9, 11, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Mueller et al. (The GOX/CAT system: A novel enzymatic method to independently control hydrogen peroxide and hypoxia in cell culture, Advances in Medical Sciences · Vol. 54(2) · 2009 · pp 121-135, cited in PTO-892) and Wang et al. (A novel experimental hypoxia chamber for cell culture, Am J Cancer Res 2014;4(1):53-60, cited in PTO-892)
Regarding claim 1, Mueller et al. teaches a novel enzymatic method to independently control hydrogen peroxide and hypoxia in cell culture. Mueller et al. describes an enzymatic oxygen-consuming system comprising glucose oxidase (GOX) and catalase (CAT), introduced into a culture medium containing glucose substrate to regulate oxygen levels, and explains that “the GOX/CAT system allows the independent and rapid control and maintenance of hypoxia and H₂O₂ in cultured cells” (pg. 122, left column). Mueller et al. further teaches that “the degree of hypoxia is dependent on the GOX activity and the diffusion distance of oxygen from the medium surface to the adherent cells”… “in contrast to hypoxia chambers, the GOX/CAT system more rapidly induces hypoxia within minutes at a defined rate”, and that “H₂O₂ levels are solely controlled by the ratio of GOX and CAT activities” (Abstract). Mueller et al. explicitly discloses oxygen rates and achieves oxygen concentration levels ranging as low as 0.5% in human hepatoma cells exposed to GOX/CAT (pg. 127, Table 2, pg. 129, Fig. 11, and pg. 130 Fig. 13). Thus, Mueller et al. discloses selecting the amounts and activities of the enzyme (GOX) and substrate (glucose) to achieve a predetermined degree and rate of hypoxia in tissue/cells. However, Mueller et al. does not explicitly disclose providing the sample of tissue in a hermetically sealed container.
Wang et al. discloses a sealed chamber used for hypoxia studies in tissue or cell culture (pg. 54, right column), corresponding to a hermetically sealed container. Wang et al. describes “a novel and inflatable chamber for hypoxia experiments … leakage-free and adjustable in size” (pg. 57, right column), and further that “this new hypoxia chamber was airtight” (pg. 56, right column) and “yielded reproducible and comparable results as the modular incubator chamber did” (Abstract). Wang therefore teaches a system capable of maintaining a sealed, oxygen-limited environment suitable for inducing and studying hypoxia in tissue or cell cultures.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to perform the enzymatic hypoxia-control method of Mueller within the sealed chamber of Wang, since Wang teaches that hypoxia chambers provide a controlled, airtight, leak-free environment for hypoxia studies, and combining the two would predictably allow improved control and reproducibility of the induced hypoxic state. Given Wang’s successful demonstration of inducing and maintaining hypoxic conditions in cell cultures using a sealed chamber for study, said practitioner would have a reasonable expectation of success in using Wang’s sealed chambers in the method taught by Mueller, to arrive at a method for assessing an effect of hypoxia on a tissue, using a hermetically sealed container according to claim 1. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claim 9, Mueller et al. discloses inducing and quantifying hypoxia in cell cultures by enzymatic consumption of oxygen (GOX/CAT system), wherein oxygen concentration in the culture medium is measured as a function of time to determine the extent of hypoxia (pg. 129, Fig. 11B). Mueller et al. further discloses that control experiments under normoxic (21% O₂) conditions are performed for comparison (see discussion of Fig. 7A, p. 126). As described above, Wang et al. teaches the use of adjustable, hermetically sealed chambers to maintain separate, defined oxygen environments for replicate samples. It would have been obvious to a person of ordinary skill in the art to employ multiple such sealed chambers to perform parallel hypoxic and normoxic incubations and measure an oxygen-dependent property (e.g., oxygen concentration or redox level) for comparison, as a routine control technique in hypoxia studies. The combination of teachings therefore renders the subject matter of claim 9 obvious.
Regarding claims 11 and 13, Mueller et al. discloses that the dissolved oxygen concentration corresponding to atmospheric oxygen levels (normoxia) is used as the reference point for establishing and restoring oxygenation levels during hypoxia/reoxygenation cycles, thereby enabling measurement of reoxygenation kinetics. Specifically, “the dissolved oxygen of 220 µmol/l O₂ corresponds to 21 % O₂ in air,” (pg. 129, last para and FIG. 11B). Furthermore, Mueller et al. teaches “hypoxia develops under conditions where oxygen consumption is larger than its replacement from air”, illustrating this principle in a cell culture dish, which has access to atmospheric oxygen at the top, with cells at the bottom (Fig. 7A), contrasting it with “the principle of the classical hypoxia chamber”, wherein “the cell culture dish is hermetically separated from the environment of 21% oxygen when flushed with a low oxygen gas mixture such as of 2% oxygen” (pg. 126, right column and Fig. 7B). Accordingly, Mueller et al. teaches the use of atmospheric oxygen as a source for reoxygenation.
Additionally, claim 11 recites “a third amount of the reaction substrate” and “a fourth amount of the reaction enzyme”, however, the preceding claims define only “a first amount of the reaction substrate” and “a second amount of the reaction enzyme”. While this numbering appears intended to distinguish reagents associated with different samples or containers, the sequential designation (first/second in claim 1; third /fourth in claim 11) is non-standard and may cause unnecessary complexity when reading the claims. Applicant may wish to amend the claims for improved clarity and consistency – for example, by referring in claim 1 to first amounts of both the substrate and enzyme, and in claim 11 to second amounts of each – or by omitting numerical modifiers altogether.
Wang et al. provides the sealed-chamber system permitting controlled introduction of oxygen into a previously hypoxic environment. It would have been obvious to modify the method of claim 9 to include a third sealed container undergoing a complete hypoxia–reoxygenation cycle to measure the same oxygen-dependent property before and after reoxygenation, since Mueller et al. explicitly teaches such comparative oxygen cycling experiments for modeling physiological hypoxia/reoxygenation responses.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, given Mueller et al.’s disclosure of (1) enzymatically induced hypoxia using a glucose oxidase/catalase system and (2) the defined reference concentration of 220 μM O₂ corresponding to atmospheric (21%) oxygen, it would have been obvious to a person of ordinary skill in the art to utilize ambient air (atmospheric oxygen) as the oxygen source for the re-oxygenation step of the method. A skilled artisan would have recognized that exposing the hypoxic tissue sample to atmospheric oxygen provides a convenient, predictable, and controllable means of restoring normoxia to the initial oxygenation level, consistent with standard cell-culture practice and Mueller’s comparative examples. Accordingly, the combination of Mueller et al. with Wang et al. (teaching hermetically sealed chambers) would have rendered the subject matter of claims 11 and 13 obvious.
Claims 2-8, 10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Mueller et al. and Wang et al. as applied to claims 1, 9, and 11 above, and further in view of Tarasev et al. (Individual Variability in Response to a Single Sickling Event for Normal, Sickle Cell, and Sickle Trait Erythrocytes, 191 Translational Research (2017) pp. 96-107, cited in the IDS).
The teachings of Mueller et al. and Wang et al. as they apply to claims 1, 9, and 11 have already been discussed above. Briefly, Mueller et al. teaches a method to independently control hypoxia in cell cultures, using GOX/CAT, teaching hypoxic and normoxic control experiments, as well as reoxygenation after deoxygenation. Wang et al. teaches that sealed hypoxia chambers provide a controlled, airtight environment for maintaining reproducible oxygen tension in replicate tissue and cell culture experiments. With respect to inducing hypoxia associated to a disease state, Mueller et al. further teaches that “GOX/CAT can be employed to address many questions ranging from redox signaling to ischemia/reperfusion studies” (Abstract) and that “the GOX/CAT system is an attractive approach for all researchers that would like to study their individual experimental culture system under close to realistic in vivo conditions” (pg. 122, left column).
Regarding claims 2-8, Tarasev et al. teaches that both normal (AA) and sickle-cell (SS) red blood cells exhibit quantifiable mechanical fragility responses under controlled hypoxia and reoxygenation cycles, noting that “a single polymerization triggered by a hypoxic environment was reported to result in reversibly (upon reoxygenation) decreased RBC deformability and increased mechanical fragility”, and that “AA subjects exhibited significantly different changes in fragility upon hypoxia, with recovery to initial values on reoxygenation” (Abstract). Accordingly, Tarasev et al. teaches that a predetermined rate and amount of hypoxia – corresponding to the deoxygenation kinetics observed in SCD blood – can be applied to replicate disease-associated morphological responses in normal or test RBCs. Tarasev et al. discloses that each blood sample was tested in “essentially oxygen-free” conditions (pg. 3, Study design), correlating to a predetermined rate and amount of hypoxia. It is noted that hemoglobin polymerization is the primary event in sickle cell disease and RBC fragility is a common feature (pg. 2, Introduction). Therefore, the hypoxic conditions described above correlate to a predetermined rate and amount of hypoxia associated with the disease state observed in sickle cell disease.
Regarding claims 3-4 and 8, Tarasev et al. reports that hemoglobin within RBCs cycles between deoxygenated (Deoxy-Hb) and oxygenated (Oxy-Hb) states during repeated hypoxia/reoxygenation cycles. Tarasev et al. discloses values for RBCs during states of oxygenation, deoxygenation, and reoxygenation, allowing for determination of the rate/concentration of deoxygenation over time. Regarding reoxygenation, Tarasev et al. discloses “reoxygenation to essentially 100% Oxy-Hb was also confirmed using STS spectrophotometer” (pg. 3, Study design).
Regarding claim 7, as described above, Tarasev et al. teaches the exposure of RBCs to controlled hypoxic and reoxygenation conditions produces changes in morphology and mechanical fragility. Given Mueller et al. disclosure of enzymatic, independently controlled induction of hypoxia, a person of ordinary skill in the art would have recognized that the degree and rate of oxygen depletion could be tuned to achieve any desired hypoxic profile. In view of Tarasev et al. teaching that specific deoxygenation kinetics determine the extent of red blood cell deformation and fragility characteristic of sickling, said practitioner would have been motivated to optimize the hypoxic conditions in Mueller et al. to replicate a particular sickled morphological form observed in sickle cell disease. Thus, it would have been obvious to adjust the predetermined rate and amount of hypoxia in Mueller et a. so as to correspond to the morphological outcomes described by Tarasev et al.
Regarding claims 10 and 12, Tarasev et al. teaches measurement of mechanical fragility (MF) of red-blood-cell membranes as a direct response to hypoxia and reoxygenation, noting that “mechanical stress was applied to RBC samples with the use of a TissueLyser LT bead mill…”[pg. 3, Mechanical fragility test]. Tarasev et al. discloses averages values for mechanical fragility observed across all RBC samples (pg. 5, Table II and Fig. 2-4).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, given Mueller’s teaching of regulating oxygen depletion rates, Wang’s teachings of sealed chambers for reproducible hypoxia control, and Tarasev’s demonstration that controlled hypoxic exposure in normal RBCs can model disease relevant stress responses characteristic of sickle-cell pathology, a person of ordinary skill in the art would have been motivated to employ the combined system to mimic the hypoxia-induced mechanical fragility changes observed in SCD, using blood samples as a physiological model. Such a combination would have been a predictable use of a known hypoxia control and measurement technique to reproduce disease associated oxygenation kinetics for experimental study, mimicking realistic in vivo conditions, as noted by Mueller. Said practitioner would have a reasonable expectation of success given Mueller’s successful demonstration of utilizing GOX/CAT to induce varying degrees of hypoxia, and even anoxic states, in cell cultures, and Tarasev’s successful demonstration of hypoxic induced pathology using RBCs from normal patients, alongside sickle cell patients. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
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.
Claims 1-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11662353. Although the claims at issue are not identical, they are not patentably distinct from each other because US Patent ‘353 claims clearly anticipate instant claims.
Claims 1, and 4-7, and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11933780. Although the claims at issue are not identical, they are not patentably distinct from each other because US Patent ‘780 claims anticipates instant claims.
It is noted that in the ‘780 claims, “a predetermined rate of oxygen consumption” is understood as being synonymous with “a predetermined rate of hypoxia”.
Conclusion
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NAGHMEH NINA MOAZZAMI whose telephone number is (703)756-4770. The examiner can normally be reached Monday-Friday, 9:00-5:00.
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/NAGHMEH NINA MOAZZAMI/ Examiner, Art Unit 1652
/RICHARD G HUTSON/ Primary Examiner, Art Unit 1652