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 .
Response to Amendment
The amendment filed 9/29/2025, amending claim(s) 1, 3, and 7 is acknowledged. Claims 1, 3, and 7 are pending and under examination. Applicant’s amendments to the claims have overcome each and every claim and drawing objection, 101 rejection, and 112(b) rejection of claim 3 previously set forth in the Non-Final Office Action mailed 3/28/2025. Additionally, the 102 rejection of claims 1, 3, and 7 as being anticipated by Kiko is withdrawn. Kiko does not teach the new limitation of “wherein the red blood cell preparation has been treated ex vivo to reduce the level of oligomers or aggregates of proteins”.
Drawings
The drawings filed 9/29/2025 are accepted.
Claim Interpretation
A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The phrase "to reduce the level of oligomers or aggregates of proteins" is an intended use limitation, which does not contain any further structural limitations with respect to the claimed [e.g. a treated red blood cell preparation] (see MPEP §2114).
Claim Rejections - 35 USC § 112(a) – New, necessitated by amendment
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, 3 and 7 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.
Claim 1 recites a treated red blood cell preparation derived from one or more of the following:
a donor or donors,
the subject's red blood cells
stem cells or other mononuclear cells; and
from a xenotransfusion source,
wherein the red blood cell preparation has been treated ex vivo to reduce the level of oligomers or aggregates of proteins, and
wherein the level of oligomers or aggregates of proteins in the red blood cell preparation has been measured and shown to be at a reduced level as compared to the red blood cell preparation prior to treatment.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The breadth of the claimed genus of sources of cells for the claimed preparation reasonably encompasses any type of cell from any source or species (e.g., xenotransfusion); as written, the claims do not require the source of the red blood cell preparation to be from the blood cells of donors or xenotransfusion sources, and encompasses cells that have no/minimal amounts of oligomers or aggregates of proteins. In addition, the claim recites “stem cells or other mononuclear cells” (the examiner notes that stem cells are not considered a type of mononuclear cell, as mononuclear cells are a type of white blood cell), which reasonably encompasses any stem cell from any source at any stage of differentiation.
Additionally, the breadth of the claimed genus of oligomers and aggregates of proteins reasonably encompasses any oligomer and aggregates of any protein. Claim 7 further specifies what the oligomer or aggregated proteins must comprise, which still reads on any oligomer and aggregates of any protein being present along with one of those listed in claim 7.
The breadth of the claimed genus of ex vivo treatment methods reasonably encompasses any process that would result in a reduction of level of oligomers or aggregates of proteins. The claims fail to further limit how the red blood cell preparation may be treated. Page 7-8 of the specification generically recites
“The ex vivo process can involve the use of compounds that reverse the aggregation status of oligomeric and aggregated proteins, in this case the compounds and the resulting monomeric forms can be removed in a dialysis or other washing procedure, such as centrifugation, prior to administering the treated red blood cell preparation to the subject. Optionally the monomeric forms of the proteins that result from this treatment can be removed by an affinity adsorption step using a specific binding agent such as an antibody or a synthetic antibody such as an aptamer or a specific binding polymer prior to administering the further treated blood cell preparation to the subject. The monomers can also be separated from red cells using non-specific binding techniques such as ion-exchange or size exclusion chromatography.”
“Optionally the ex vivo process involves the removal of leukocytes prior to the addition of disaggregation compounds. This can be achieved by size filtration, continuous or intermittent flow centrifugation or the use of specific leukoreduction filters. This step also serves to remove any toxic oligomeric forms of proteins that may be associated with the leukocyte membranes.”
Page 8 further lists examples of examples of compounds suitable for reversing the aggregation status of oligomeric and aggregated proteins.
Further, the breadth of the claimed genus of measurement methods reasonably encompasses any method that would show differences in levels of oligomers or aggregated proteins. Claim 3 further limits the cells to be measured with an analytical method, which is still a vastly broad genus. The specification fails to disclose any further parameters regarding analytical methods, reciting
“The analytical method determines the presence and level of the oligomeric forms of certain proteins in the blood of the patient prior to commencing treatment and monitors the reduction in the level as the red cell replacement therapy progresses.
The analytical method can be used to determine when the red cell replacement therapy should be repeated if levels of the oligomers exceed a predefined threshold. The analytical method can also be used to confirm that the source of the red cells is free of the oligomeric forms and can also be used to confirm that the ex vivo treatment process of donor or subject blood has been successful in reducing the levels of the oligomeric or aggregated protein forms present.” (pg. 9)
The claims fail to recite, and the specification fails to disclose, the structure/function nexus of the vast genus of ex vivo treatments that necessarily and predictably possess the functional property of reducing levels of oligomers or aggregated proteins.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the red blood cell preparation is to be treated ex vivo does not tell you anything at all about the structure of the enormously vast genus of about structurally and functionally undisclosed ex vivo treatment methods (and resulting treated red blood cell preparations) having the functional property of reducing levels of oligomers or aggregates of proteins.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed class of ex vivo treatment methods (and resulting treated red blood cell preparations) includes an enormously vast genus of about structurally and functionally undisclosed ex vivo treatment methods (and resulting treated red blood cell preparations) having the functional property of reducing levels of oligomers or aggregates of proteins.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the enormously vast genus of about ex vivo treated red blood cell preparations having the functional property of reduced levels of oligomers or aggregated proteins. The claimed invention is recited at a high level of generality, and the specification fails to provide enough guidance over the breadth of the pending claims.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 112(b) - Maintained
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, 3, and 7 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 “reduced level” in claims 1 and 3 is a relative term which renders the claim indefinite. The term “reduced level” 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. It’s unclear how an artisan would define and determine what a “reduced level” is.
If there are multiple ways to measure "reduced level", such as with different analytical method(s), yet each yields a different result, it is unclear which method is to be performed and which reference is to be used to determine infringement. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 102 - Maintained
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.
Claim(s) 1, 3, and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Iofrida (Iofrida, C., et al. "Influence of physical exercise on β-amyloid, α-synuclein and tau accumulation: an in vitro model of oxidative stress in human red blood cells." Archives Italiennes de Biologie 155.1/2 (2017): 33-42.).
As discussed in the previous office action filed 3/28/25 (re-iterated below), the recitation of “wherein the level of oligomers or aggregates of proteins in the red blood cell preparation has been measured and shown to be at a reduced level” is interpreted to not limit the structure or function of the cells in any way and is solely descriptive of the natural character of red blood cells and their protein levels.
Regarding claim 1, since the claims are directed to a composition (i.e., product), the process language of the claims is evaluated to determine if the process imparts a structure or function not previously recited (i.e., if the process language is further limiting). Claim 1 recites “measuring”, imparting the limitation of evaluating a function of the claimed invention. The additional element does not limit the structure or function of the cells in any way and is solely descriptive of the natural character of red blood cells and their protein levels. As such, measuring does not impart any structural limitation. Therefore, this recitation does not further limit the claimed invention.
Iofrida discloses comparing the content of Aβ (claim 7), α-syn and tau in red blood cells (RBCs) derived from ten endurance athletes (ATHL) and ten sedentary volunteers (SED) before and after in vitro oxidative stress treatment (i.e., red blood cell preparation has been treated ex vivo to reduce the level of oligomers or aggregates of proteins- although Iofrida recites “in vitro” treatment, the disclosure of Iofrida is interpreted to read on “ex vivo”, as the cells treated were derived from an organism and the cells were maintained outside their native organism; see ex vivo definition by Medical Dictionary). Total Aβ, α-syn and tau were quantified in RBCs (isolated from the subjects) by immunoenzymatic assays (i.e., an analytical method) (Abstract). Iofrida discloses that following oxidative stress, Aβ and α-syn content in RBCs were lower in the ATHL subgroup with respect to the SED one (Abstract).
Claim(s) 1, 3, and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stanley (WO2017/067672 A1, cited in Specification).
Stanley discloses detecting and analyzing structural forms of proteins in a biological sample as part of a process to diagnose a neurological disease. Specifically, Stanley discloses measuring total Abeta and total aggregated forms in whole blood in young normal controls and AD patients using ELISA (pg. 39, Example 9; pg. 41, Example 11). Additionally, levels of aggregated Abeta, alpha synuclein, and tau in whole blood from dementia and Parkinson’s Disease (PD) patients were also tested (pg. 42, Example 12). Table 6 shows that age matched controls had lower levels of Abeta, alpha-synuclein, and tau compared to AD, dementia, and PD patients. Further, Stanley discloses the use of protein solubilizing agents and chaotropic agents to displace, disrupt and solubilize all forms of Abeta from cell surfaces or protein complexes in the cellular fraction of blood (i.e., protein solubilization is the process of breaking interactions involved in protein aggregation- see BioRad). Stanley also discloses the use of beads derivatized with Protein A (GE Healthcare, magnetic Sepharose, diameter 50 μιη to 100 μιη) were coated with mouse monoclonal anti Abeta antibody in combination with protein solubilizing and disrupting reagents in order to immunocapture of all forms of the spiked protein (Abeta 1-42) in the blood matrix (i.e., collecting cells from an organism then treating is interpreted to read on ex vivo treatment) (pgs. 25-27, Example 1).
Response to Arguments
Applicant's arguments filed 9/29/2025 have been fully considered but they are not persuasive. Regarding the 112(b) rejection of “reduced level” being a relative term that renders the claims indefinite, applicant argues that claim 1 have been amended to clarify the subject matter and that the claims should be free of this rejection. This argument is not persuasive because as discussed in the 112(b) rejection above, the amended claim language (i.e., adding the limitation of comparing levels to those prior to treatment) still does not address how an artisan would define and determine what a “reduced level” is.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638