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 .
Priority
This application is a National-Stage entry of PCT/CN2021/112093, filed 8/11/2021. Applicant’s claim for the benefit of a prior-filed application CN2020108496, filed 8/11/2020, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 6/8/2023 and 12/20/2024 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
The information disclosure statement filed 11/03/2025 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered. Specifically, no English language translation was provided for the foreign language references: JP2019-528269; JP2023-534363; and JP Application No. 2023-5511637. The foreign patent reference WO2020/086469 has been fully considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Election/Restrictions
Applicant’s election without traverse of Group 1-9 and 26), in the reply filed on 10/13/2025 is acknowledged. Claims 18-25 and 27-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-9 and 26 are pending and are examined on the merits herein.
Drawings
The drawings are objected to because Figure 12 recites the label “Protgen”. This is the name of a source of the product, not an identifier of the particular material. The drawing is objected to for lack of clarity. It can be inferred from the specification that the label should instead read “rHSA” (page 15). Correction is requested.
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.
Claim Interpretation
The following terms recited in the claims have been interpreted according to the definitions provided in the specification, in accordance with the level of ordinary skill in the art.
The specification states that the term "young and undamaged", as used in the preamble of claim 1, means that the HSA protein is in a fresh status and does not “have extensive damages as compared to a specific HSA preparation”, and the specification gives an example of “a HSA preparation obtained from an individual of 30 years old”. Under the B.R.I. of the terms, in view of the specification, the element of “young and undamaged” HSA is being interpreted as rHSA, with minimal medication, and without exposure to oxidation or proteolytic chemicals (i.e. sources of “damage” to a protein). The specification also states: “A skilled artisan will understand that the term "young and undamaged" HSA does not strictly require that there is absolutely no damage. It is very difficult, if not totally impossible, to prepare such perfect preparations. For the purpose of the present invention, a HSA preparation comprising limited damages is still acceptable.” From the disclosure, under the B.R.I. of the claim, any recombinantly-produced HSA meets this limitation of the preamble.
In claim 26, the term "pharmaceutically acceptable carrier" is being interpreted as encompassing “any of the standard pharmaceutical carriers, buffers and excipients, including buffered saline solution, water, and emulsions (such as an oil/water or water/oil emulsion), and various types of wetting agents and/or adjuvants” (see specification, page 4).
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 1-9 and 26 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.
The term “compared to an endogenous HSA preparation obtained from a young individual of human” in claim 1 is a relative term with no accepted meaning in the art which renders the claim indefinite. The term “young individual of human” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
In this case, the claim requires that the human serum albumin (HSA) protein preparation has at least one property, of (1)-(4), that is at a desirable level compared to the “endogenous” HSA preparation. The subject matter is indefinite as there is no commonly accepted standard on which to base the comparison- the comparison being essential for setting forth the boundaries of the claim. Without a numeric standard, such as those provided in claims 4-8, there is no possible manner to determine if any given preparation of HSA fulfills the limitation. In biology and medicine, it is known that there exists a great amount of variation and unpredictability among proteomics of individual subjects, even among those younger than 30, as limited by claim 2. Claim 2 also fails to address the problem of the relative comparison. There is no definition or standard that sets the level for the claimed HSA to be compared against. Some samples obtained from a “young individual below age of 30” might have extremely high AGE or carbonylation levels, whereas others could be negligible. Even considering an average or a median value, there is no defined population in the Application from which one can calculate such a value.
As another concern, because the amount of free or linked thiols of cysteine residues is sensitive to reducing and oxidizing (redox) conditions, one having ordinary skill in the art would recognize that a collected preparation of HSA, once collected and tested may be incredibly different than those endogenous proteins found within a living subject. Indeed, the redox status of such residues would be heavily influenced by the manner in which the sample is obtained, including the extraction conditions, the sample storage buffers, and the pH used (see Specification, page 20, Albumin purification).
The properties (1)-(4) in claim 1 also refer to relative terms, “higher” and “lower” which renders the claim indefinite. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Therefore, the metes and bounds of the claimed HSA preparation in claims 1-2, 9, and 26 is indefinite, as the claimed properties are compared to another variable preparation, and not to any defined numeric value or to a common accepted standard in the art (MPEP § 2173.05(b).II discusses reference to another object that is variable).
Claim 1 recites the term “Cys-34”. This is in reference to an amino acid, a specific residue in the protein sequence. However, there is no recited reference in the claim for which one to determine the identity of “Cys-34”. Further, no such sequence for a human serum albumin protein is in the application as filed. The resulting claim is indefinite as the meaning of “Cys-34” cannot be readily determined for any HSA preparation. The specification on page 5 states that “Wild type HSA (Gene name: ALB; NCBI 1D:213; UniProtKB-P02768) contains one reduced cysteine residue (Cys-34 residue)”. Because this reference has been included in the Application as filed, reference to the sequence therein by the accepted identified would be an acceptable means to delineate the meaning of “Cys-34”.
Claim 3 recites “the ratio of free thiol in Cys-34 residue is greater than 50%”, and claims 4 and 8 each recite “the ratio of free thiol in Cys-34 residue is greater than 80%”. The claim language recites a “ratio”, but describes the amount in terms of a percentage, or a proportion, which must have a denominator or a total. No total is defined in the claims. The language, as claimed, could be interpreted as a ratio of free Cys-34 to oxidized Cys-34 or a proportion of free Cys-34 to the total amount of protein. The specification provides an example of the meaning of “ratio of free thiols in HSA”, however this is not being considered a limiting definition.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The claim is indefinite because the specification does not clearly redefine the term ratio. The claims are indefinite as “50%” could mean that there is 50% free thiol compared to oxidized thiol (which would amount to a ratio of free: oxidized of 1:2), or it could mean that there is 50% free thiol to total thiol, which is the common meaning of a percentage (but a ratio of free:oxidized of 1:1).
Claim 3 recites “the Ellman’s method”, for which there is no antecedent basis in the claims. The specification recites Ellman’s method, but there is no description or definition of the method provided. No incorporation by reference statement is provided to a reference that would adequately define the Ellman’s method that is used. Therefore, this claim element is indefinite as there is no defined manner in which the testing assay is to be performed.
Claim 3 recites the limitations “Protein Carbonyl Content Assay Kit (Abcam, ab126287)”, “(CLOUD-CLONE Co., CEB353Ge)”, and “(Jianglai, JL10022)”. Some of these elements are provided in parenthetical, which renders the claim indefinite because it is unclear whether the limitations in the parenthesis are part of the claimed invention, or if they are exemplary. See MPEP § 2173.05(d).
Further, these elements recited in claim 3 include trademarks or trade names used in commerce (i.e. ABCAM, CLOUD-CLONE), and/or refer to specific product numbers (i.e. “CEB353Ge”, “Jianglai JL10022”). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe specific tests for the claimed properties of the protein and, accordingly, the identification/description is indefinite. It is unclear from the claim language if these tests, provided from specific manufacturers, are absolutely required for the claimed subject matter. The resulting claim is indefinite for all of the reasons described above.
For comparing the claimed properties of claim 3 against the prior art, the claimed properties have been interpreted according to the B.R.I. of the claims as reciting inherent or innate properties of an HSA protein. The manner in which the properties are tested does not affect the presence or lack of the chemical modification on the claimed composition.
Claim 8 recites four specific limitations regarding the tested properties of the preparation, however the claim does not recite a conjunction such as “and” or “or”, and thus one cannot determine the metes and bounds of this claim. Are these all required of the claim? Or should this be presented in a similar manner to claim 1, which uses the language “at least one or all of”.
All other claims depend directly or indirectly from the rejected claims and are, therefore, also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the reasons set forth above.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-9 and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
For determining subject matter eligibility, the following analysis was considered, per MPEP § 2106.
Patent Eligibility Analysis Step 1: Step 1 of the eligibility analysis asks: is the claim to a process, machine, manufacture or composition of matter? Yes, the claims are directed to a composition. (Claims 1-9 and 26, STEP 1: YES).
Patent Eligibility Analysis Step 2A Prong 1: Step 2A, prong 1 asks: does the claim recite an abstract idea, law of nature, or a natural phenomenon (a product of nature)?
Claim 1 recites a preparation, a composition, of human serum albumin comprising at least one or all of the following properties: (1) higher ratio of free thiol in Cys-34 residue, (2) lower level of advanced glycation end-product (AGE), (3) lower level of carbonylation, and (4) lower level of homocysteinylation, as compared to an endogenous HSA preparation obtained from a young individual of human.
Dependent claims 2-8 recite additional limitations regarding the properties of the HSA.
Claim 9 recites that the preparation is produced recombinantly or purified from plasma.
Claim 26 recites a pharmaceutical composition, comprising the preparation of young and undamaged human serum albumin as defined in claim 1 and a pharmaceutically acceptable carrier, which includes buffered saline solutions, water, and emulsions.
The claims recite a natural product, the preparation of human serum albumin.
Thus, the B.R.I. of claims 1-9 and 26 includes limitations encompassing natural products.
The disclosure discusses the use of freshly prepared recombinant serum albumin (see page 11 and Figure 12). The instant claims encompass a natural HSA protein having none of the recited modifications. MPEP § 2106.04(c)I. states that “if the nature-based product limitation is naturally occurring, there is no need to perform the markedly different characteristics analysis because the limitation is by definition directed to a naturally occurring product and thus falls under the product of nature exception”. In the instant case, a fully unmodified HSA with no exposure to oxidizing conditions and having no modifications appears to fall under this definition. However, if the claimed preparation could be considered a nature-based product having some man-made intervention, affecting to some extent the claimed characteristics of the properties compared to the natural product, then the markedly different characteristics (MDC) analysis below has been applied.
When a claim recites a nature-based product limitation, the markedly different characteristics (MDC) analysis is used to determine whether the natural product has markedly different characteristics from its natural counterpart (MPEP 2106.04(c)).
The first step is to determine the appropriate natural counterpart for the claimed product to be compared against. In this case, the appropriate natural counterpart for the preparation of human serum albumin of claims 1-9 would be a natural HSA protein.
For claim 26, the proper comparison is to the HSA protein, in a carrier within the limits of the claim, including water or a buffered solution (i.e. a naturally occurring buffered solution such as plasma). MPEP § 2106.04(c) explains “Where the claim is to a nature-based product produced by combining multiple components, the markedly different characteristics analysis should be applied to the resultant nature-based combination, rather than its component parts.”
The second step in the MDC analysis is to identify appropriate characteristics to compare. Appropriate characteristics can be expressed as the nature-based product’s structure, function, and/or other properties, and are evaluated on a case-by-case basis. In this case, the appropriate characteristics include: biological functions or activities, phenotypic characteristics which include functional and structural characteristics such as the shape, size, color, and behavior of an organism, and structure and form (chemical, genetic or physical) of the natural components. These include the sequence and structure of the HSA, which is unchanged from the natural product. The functional and chemical properties include, but are not solely limited to therapeutic effects, the amino acid sequence, molecular weight, the ratio of free thiol in Cys-34 residue, the amounts of glycation end-product (AGE), the lower level of carbonylation, and/or the levels of homocysteinylation, which are recited in the disclosure.
The final step in the markedly different characteristics analysis is to compare the characteristics of the claimed nature-based product to its naturally-occurring counterpart in its natural state, in order to determine whether the characteristics of the claimed product are markedly different. The courts have emphasized that to show a marked difference, a characteristic must be changed as compared to nature, and cannot be an inherent or innate characteristic of the naturally-occurring counterpart or an incidental change in a characteristic of the naturally occurring counterpart. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75.
In order to be markedly different, the inventor must have caused the claimed product to possess at least one characteristic that is different from that of the counterpart (MPEP § 2106.04(c).II.C.). If there is no change in any characteristic, the claimed product lacks markedly different characteristics, and is a product of nature exception.
No characteristics of the naturally-derived product are markedly changed by a process of purification, nor is there any disclosure of a difference from the instantly claimed protein preparation and the “young and undamaged” HSA protein as it exists in nature, according to the interpretation described above. Detecting the presence or amount of a natural phenomenon is not patent eligible, see MPEP§2106.04(c).I.C: "the existence and location of cffDNA is a natural phenomenon [and thus] identifying its presence was merely claiming the natural phenomena itself." Rapid Litig. Mgmt., 827 F.3d at 1048, 119 USPQ2d at 1374, (explaining the holding in Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 115 USPQ2d 1152 (Fed. Cir. 2015))”.
Turning to the literature, one can determine that HSA proteins with none (i.e. with free or reduced thiol) or varying amounts of oxidative modifications are found naturally.
Era et al. (“Age-related change in redox state of human serum albumin.” Biochimica et biophysica acta vol. 1247,1 (1995): 12-6, cited in the specification) demonstrates that in healthy, 20-yr old humans, HSA in the reduced form (termed therein human mercaptalbumin, or HMA) was found at a mean value of 0.76 + 0.04 (n = 54), and in older individuals at a fraction of 0.48 + 0.06 (n = 183) (Abstract). Era teaches that it is known that HSA/HMA has one free sulfhydryl residue in position 34 (Cys-34) (pg. 12, left col). Interestingly Era also demonstrates that time-dependent changes of f(HMA) values in HSA, depending on the temperature it is stored at (see Table 2). Thus, Era et al provides evidence that the relative amount of free thiol at Cys-34 of HSA is a natural and condition/environment dependent property of the protein.
Anguizola et al. ("Glycation of human serum albumin." Clinica chimica acta 425 (2013): 64-76.) discusses measurements of glycated albumin, with an interest in using glycation of albumin as an indicator for glycemic control in diabetic patients, and discuss the natural phenomena involving the formation of Advanced glycation end-product, or AGE (see Abstract, Figure 1). See also Table 1 of Anguizola, describing a number of modification sites and adducts that have been reported for glycated human serum albumin (HSA). Anguizola states that studies estimate that 6–13% of HSA is glycated in healthy individuals, with this amount increasing by up to 20–30% in diabetic patient (see pg 67, left col, 2nd para). Thus, naturally occurring HSA may be found with minimal glycation and with extensive modification including AGEs.
Jana et al. (“Specificity of age-related carbonylation of plasma proteins in the mouse and rat.” Archives of biochemistry and biophysics vol. 397,2 (2002): 433-9, cited in the instant specification) teaches that, at least in mice and Rhesus monkeys, the amount of carbonylation of plasma albumin increases with age (Abstract), and states that this is a natural selective phenomenon. Jana suggests that carbonylated albumin can be a possible marker of oxidative damage in the plasma (pg 438, final paragraph).
Colombo et al. (“Redox Albuminomics: Oxidized Albumin in Human Diseases.” Antioxid. Redox Sign. 17, (2012):1515-1527, cited in the instant specification) reviews the role of modified albumins in oxidative stress and suggests that the albumin redox state may serve as a global biomarker for the redox state in the body in various human diseases (Abstract). Colombo states: “In plasma of healthy young adults, 70%– 80% of total HSA contains the free sulfhydryl group of Cys34” (page 1518, left col). Colombo also discloses that carbonylated albumin (Alb-CO) is present in high levels in various human diseases and pathophysiological conditions (see Table 2, and pages 1519-1521).
Jakubowski (“Homocysteine is a protein amino acid in humans. Implications for homocysteine-linked disease”. J. Biol. Chem. 277, 30425-30428 (2002), cited in the instant specification) describes that homocysteine bound by amide or peptide linkages (Hcy-N-protein) is present in human serum albumin (Abstract, Table II). Jakubowski discloses that for human albumin homocysteine modified protein was up to 2.8 ± 0.7 µM (in 50mg/mL of albumin).
Regazzoni et al. (“Human serum albumin cysteinylation is increased in end stage renal disease patients and reduced by hemodialysis: mass spectrometry studies.” Free radical research. 2013 Mar 1;47(3):172-80. DOI: 10.3109/10715762.2012.756139), discloses covalent modifications of human serum albumin (HSA) in end stage renal diseases (ESRD) non-diabetic patients and age-matched healthy subjects (n = 10, 20–60 yr) (Abstract), including the natural occurrence of homocysteinylation (pg. 172, right col, and Figure 2). Regazzoni also states that “As a further confirmation, we found that HSA-Cys is significantly elevated in older subjects as compared to HSA-Cys in younger subjects” (pg. 178, right col).
The cited art and the instant disclosure provide substantial evidence that there are no markedly different characteristics of the claimed composition when compared to naturally-occurring HSA, as the levels of modification are variable in vivo, and the claims encompass newly produced, fully reduced HSA, having no oxidation or modification.
Thus, after consideration, the recited chemical properties and modifications (or lack thereof) amount to nothing more than naturally occurring phenomena, and the claimed HSA having low amounts of one or more of these is not markedly different than natural HSA, obtained from a young or healthy subject, or even to HSA obtained from an in vitro cultured cell.
Regarding a recombinantly-produced protein, if the protein is identical in characteristics to the naturally occurring product, then the manner in which it is produced is immaterial to the eligibility, unless there is substantial evidence of a changed property, compared to its natural counterpart, in this case naturally occurring HSA protein. See MPEP § 2106.04(c).I.B.
The claimed subject matter encompasses a HSA protein having none of the recited modifications. Such a protein, either produced recombinantly or purified would not have any markedly different characteristics or functional properties than the natural protein.
When considering the composition of claim 26, there is no evidence or suggestion that the claimed product has any markedly different characteristic than a combination of the individual naturally occurring products, i.e. the natural protein without any modifications in a natural aqueous solution, including but not limited to water or plasma.
Therefore, the claimed product lacks markedly different characteristics, and is a product of nature exception (Claims 1-9 and 26, Step 2A, Prong 1: YES).
Patent Eligibility Analysis Step 2A Prong 2: Step 2A, prong 2 asks: does the claim recite additional elements that integrate the judicial exception into a practical application?
Claims 1-8 do not recite any additional elements other than the product of nature exception and intrinsic properties thereof, as set forth above. These claims do not integrate the judicial exception into a practical application because the functional limitations merely reflects innate capabilities of the natural product, as determined from comparison to another natural product. The modifications are in fact themselves drawn to naturally occurring phenomena, and there exists evidence of naturally occurring HSA having none or low amounts of these modifications. Further, these elements do not require a particular or directed application.
Claim 9 recites that the protein is produced recombinantly or is purified, but this doesn’t differentiate the claims from the natural product, nor does it recite a practical application thereof.
Claim 26 recites a pharmaceutical composition having a suitable carrier, but this does not apply the judicial selection in any specific and practical application. There is no practical application or implementation of the natural product recited.
Therefore, the judicial exception is not integrated into a practical application because the claims do not recite any additional elements other than the naturally-occurring product(s) and innate functional characteristics thereof (Claims 1-9 and 26, Step 2A, Prong 2: NO).
Patent Eligibility Analysis Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
The recitation of an innate property or characteristic of a natural product does not result in significantly more than the judicial exception. In this case, the B.R.I. of the claims, even in view of the additional elements, encompasses a recombinant HSA protein preparation with only free thiol at Cys-34 (i.e. no oxidation), with no AGE, no carbonylation, and no homocysteinylation. In other words, the fully natural HSA protein, having none of the recited modifications, would still be a natural product, as this is a naturally occurring protein.
Further, the art cited above together with the evidence from the specification indicates that naturally occurring human protein can have varying levels of these four chemical modifications, depending on the age and health status of the individual. These chemical modifications are also naturally occurring. Therefore, regardless of the amounts of reduced Cys-34, AGE, carbonylation, and/or homocysteinylation present, the claims continue to be directed to an ineligible natural product, and not to significantly more.
None of the additional elements recited in claims 2-9 amount to significantly more than the ineligible natural product when the claim is considered as a whole. These limitations do not practically limit the claims to transformed structures, or anything other than the natural product, instead these merely recite specific elements or functional properties of the product.
Regarding claim 26, the B.R.I. of the pharmaceutical carrier encompasses solutions, i.e. water, phosphate buffers, emulsions, which are themselves natural products, and thus these cannot be considered an additional element that amounts to significantly more than the ineligible natural product. As a whole, the claimed product would not be significantly different from naturally occurring HSA found in plasma or in an aqueous buffer.
When considered individual or in combination, the claims do not amount to more than the judicial exception.
Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (Claims 1-9 and 26, Step 2B: NO).
As such, the claims do not qualify as eligible subject matter. For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 8-9, and 26 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Jorgensen (US PGPub No. 20190216079).
Jorgensen pertains to recombinant yeast-derived serum albumin preparations and uses thereof (Abstract). Jorgensen discloses yeast-derived serum albumin preparations comprising predominantly a native intact human serum albumin molecule, with a reduced Cys34 residue ([0396]). Jorgensen also discloses that “the yeast-derived recombinant serum albumin preparation comprise albumin protein that has a free thiol group content (specifically, at Cys34) that is greater than 62%, such as at least 69%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, about 96%, about 97%.” ([0400]).
Thus, Jorgensen discloses a preparation of “young and undamaged” (i.e. substantially pure and unmodified- according to the B.R.I. of the claim) recombinant human serum albumin (HSA), that exhibits at least the property of a higher ratio of free thiol in the Cys-34 residue ([0400]: “at least 95%, about 96%, about 97%”) than an endogenous HSA preparation obtained from a young human subject (as best understood from the specification to be a minimum of 50%, but could be greater, up to 70-80%), as recited in claim 1.
Regarding claim 2, there doesn’t appear to be any structural difference in the recitation that the young human is of age 30, in terms of the claimed preparation. Jorgensen discloses recombinant HSA with a free thiol percentage of up to about 97%, which appears to be in accordance with the findings of the instant specification regarding the claimed subject material.
In regards to claim 3, the claim recites inherent or innate properties of an HSA protein wherein the manner in which the properties are tested does not affect the presence or lack of the chemical modification on the claimed composition. Claim 3 is being interpreted as requiring, among other options, that the ratio of free thiol in Cys-34 residue is greater than 50%. The recombinant HSA preparation of Jorgensen has an amount of free thiol at the Cys-34 residue which is greater than 50% ([0400]: “greater than 62… at least 95%, about 96%, about 97%”). Jorgensen is not explicit that the free thiol is tested with “the Ellman’s method”, however the free thiol amounts of the preparation therein are greater than or are the same as those of the instant claim, regardless of the method by which it is determined.
Regarding claim 4, Jorgensen discloses recombinant HSA with a free thiol percentage of up to about 97%, which is more than the claimed 80%.
Claim 8, as explained above, has been interpreted as reciting a Markush-type list of alternative properties for the claimed preparation. Of note, the claim does not explicitly say “and”. Thus, claim 8 is found to be anticipated by Jorgensen for the same reasons as claim 4.
Regarding claim 9, the preparation of Jorgensen is clearly recombinant.
Regarding claim 26, one embodiment of Jorgensen recites a cryopreservation medium, that comprises a recombinant yeast-derived serum albumin preparation, a cryopreservant, and an ionic buffer, which comprises or consists of, an aqueous solution of electrolytes, and wherein preferably, the ionic buffer possesses electrolyte concentrations, osmolality and/or pH that mimics that of human physiological plasma ([0057]). This preparation contains the recombinant HSA having the chemical property of reduced free thiol at Cys-34, as discussed above, and at least on pharmaceutically acceptable carrier, as the ionic buffer clearly is a carrier or excipient, according to the B.R.I. of the claim term, as set forth previously.
For these reasons, claims 1-4, 8-9, and 26 are considered to be anticipated by the disclosed recombinant human serum albumin of Jorgensen.
Claim Rejections - 35 USC § 102/103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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 and 26 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Goodley (US Pat No. 5,728,553, on the IDS filed 12/20/2024).
Goodley discloses a process for the preparation of albumin which has extremely low levels of or is essentially free of colorants, metal ions, human proteins, fragments of albumin, polymers or aggregates of albumin, and viruses, and which is relatively non-glycated, relatively high in free thiol and with an intact C-terminus (Abstract). The process in Goodley teaches comprises passing albumin (preferably expressed and secreted by transformed yeast) through two chromatography purifications, ultrafiltering the product, passing through two further chromatography steps and again ultrafiltering the product (Abstract, Claim 1). Goodley specifically discloses human serum albumin (HSA) extracted from serum, and recombinant human albumin (rHA) produced by transforming a microorganism with a nucleotide coding sequence encoding the amino acid sequence of human serum albumin (Col 1, lines 10-16).
Goodley states that the prepared albumin therein has, among other properties, a free thiol content of at least 0.85 mol SH/mol protein, i.e. a ratio of at least 0.85 free thiol to total thiol (Col 2, lines 3-4). Goodley also discloses that free thiol is tested with Ellman’s Reagent, demonstrates testing prior art compositions for comparison and discloses that “These values are significantly lower than the value for albumin prepared according to the example above which is routinely assayed at 0.85-0.9 mol SH/mol rHA” (Col 25, line 40 – Col 26, line 39).
Thus, Goodley discloses a preparation of “young and undamaged” (i.e. substantially pure and unmodified- according to the B.R.I. of the claim) human serum albumin (HSA), that exhibits at least the following properties: a higher ratio of free thiol than a endogenous HSA preparation obtained from a young human subject (the comparison is to an HSA having greater than 50% free thiol as discussed in the specification). Because Cys-34 is inherently the only source of free thiol in HSA, as evidenced by the instant disclosure on page 15 (“a HSA molecule theoretically has only one free thiol”), the composition of Goodley is deemed to inherently possess at least one of the required properties of the claimed young HSA preparation.
Regarding claim 2, there doesn’t appear to be any structural difference in the recitation that the young human is of age 30, in terms of the claimed preparation. Goodly discloses recombinant HSA having a free thiol content of at least 0.85 mol SH/mol protein, i.e. a ratio of at least 0.85 free thiol to total thiol (Col 2, lines 3-4). This appears to be substantially identical to the chemical property of the claimed preparation, and thus greater than an individual of age 30.
In regards to claim 3, the claim recites inherent or innate properties of an HSA protein wherein the manner in which the properties are tested does not affect the presence or lack of the chemical modification on the claimed composition. Claim 3 is being interpreted as requiring, among other options, that the ratio of free thiol in Cys-34 residue is greater than 50%. Goodley tests HSA samples with “Ellman’s Reagent” and discloses that albumin prepared according to the inventive method therein has 0.85-0.9 mol SH/mol rHA (Col 25, line 40 – Col 26, line 39), thus explicitly fulfilling at least one of the alternatives.
Regarding claim 4, Goodley discloses recombinant HSA with a free thiol percentage of up to about 97%, which is more than the claimed 80%.
Claim 8, as explained above, has been interpreted as reciting a Markush-type list of alternative properties for the claimed preparation. The claim does not explicitly recite “and”. Thus, claim 8 is found to be anticipated by Goodley for the same reasons as claim 4.
Regarding claim 9, the preparation of Goodly may be recombinant or purified from serum (Col 1, lines 10-16).
Regarding claim 26, Goodly explicitly discloses formulation steps to produce rHA in an appropriate chemical environment, wherein “formulation is complete following addition of appropriate conventional pharmaceutically acceptable excipients and diluting water, such as those specified in the U.S. Pharmacopeia for human albumin.” (Col 20, lines 51-55). Thus, Goodly is deemed to anticipate the pharmaceutical composition of claim 26.
Regarding claim 5, Goodley discloses that the HSA composition produced by the method therein is relatively non-glycated, and discloses an assay for rHA glycation, demonstrating the rHA purified in accordance with the invention is not modified by non-enzymic glycosylation (glycation) (Col 21, lines 1-5). Goodley also discloses, in some embodiments (see claim 2) that the fraction enriched in albumin is passed through an affinity matrix comprising glycoconjugate-binding and saccharide-binding compounds to yield an albumin preparation depleted in glycoconjugates and saccharides (claim 2, and Col 32, line 30- Col 34, line 6).
Therefore, although Goodley is silent regarding the presence of advanced glycated end-products, the disclosure that the albumin is non-glycated, and the extensive similarities between the extensively purified rHSA of Goodley and the instantly claimed preparation, is strong evidence that the rHSA of Goodley is intrinsically free of advanced glycated end-products.
Similarly, as the rHSA disclosed in Goodley appears to be structurally and functionally identical to that of the instant invention, the properties limited in claims 6 and 7 in regards to the amounts of protein carbonylation and level of homocysteinylation would intrinsically be present in the purified rHSA of Goodley, if measured by the same assays employed herein. The low levels of homocysteinylation is further evidenced from the very low amounts of oxidized Cys in the preparation of Goodley, to which the homocysteine is linked.
MPEP § 2112 discusses that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) and that “...The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004).”
In this case, the new, undamaged recombinant HSA produced and extensively purified according to all of the methods in Goodley appears to be identical to the preparation of HSA in the instant claims. MPEP § 2112.01.I. states that: “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Please note, since the Office does not have the facilities for examining and comparing Applicants’ composition with the composition of the prior art, the burden is on applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), and “as a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
The structurally identical HSA product of Goodley is deemed to have substantially the same properties as the composition of the instant claims, and thus the prior art product inherently possesses reduced carbonylation and low amounts of homocysteine, as instantly claimed.
In the alternative, even if the composition (with respect to the structure of the HSA) is not identical to the referenced composition and effects, with regard to unidentified characteristics, the differences between that which is claimed and that which is disclosed, is so slight that the referenced composition is likely to inherently possess the same characteristics of the claimed composition, particularly in view of the similar characteristics which they have been shown to share and by the functions of the component materials (the sequence of the amino acids, and any chemical properties thereof) which are inherently present in each and which functions are inclusive of those appreciated in the instant disclosure as being present (see MPEP § 2112.02 at Ex parte Novitski, in reference to reference-silent functioning of biological materials providing anticipation of the functions based upon the material itself - noting the reference of “Dart” therein did not appreciate the claimed function but still anticipated the function based on the inherent function of the material, and that the Applicant’s disclosure appreciating the function upon usage thereof as further evidence of the presence of the function).
Thus, the claimed composition comprising a preparation of young and undamaged HSA and any functional properties thereof, would have been anticipated, or in the alternative, at least prima facie obvious to those of ordinary skill in the art within the meaning of 35 USC § 103.
From the teachings of Goodley, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed pure and undamaged HSA preparation. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention, as evidenced by Goodley, especially in the absence of evidence to the contrary.
Accordingly, the claimed invention as a whole would have been at least prima facie obvious, if not anticipated by Goodley, especially in the absence of sufficient, clear, and convincing evidence to the contrary.
Non-Statutory 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 r