Patent: 10,271,876

Summary for Patent: 10,271,876

Title:	Method of in vitro fertilization with delay of embryo transfer and use of peripheral blood mononuclear cells
Abstract:	A method of in vitro fertilization wherein the embryo is implanted into the uterus of a female patient at least two, and preferably three to twelve months after the eggs are retrieved from the patient in order to reduce the effect of autoimmune rejection of the embryo by the patient\'s autoimmune system and increase the probability and success of pregnancy and wherein prior to embryo implantation, the endometrium in the uterus is prepared for embryo implantation by introducing peripheral blood mononuclear cells (PBMCs) into the uterus. The procedure is combined with cryopreservation techniques to preserve the oocytes or the IVF-produced embryos of the patient.
Inventor(s):	Feskov; Alexander (Kharkov, UA), Feskova; Irina (Kharkov, UA), Zhylkova; Ievgeniia (Kharkov, UA), Zhilkov; Stanislav (Philadelphia, PA)
Assignee:	MEZADATA MEDICAL IP HOLDING LLC (Dover, DE)
Application Number:	13/655,257
Patent Claims:	see list of patent claims

Executive summary: US Patent 10,271,876 (IFV PBMCs + hCG-culturing + delayed embryo transfer)

US 10,271,876 claims an IVF workflow that (i) culturing autologous peripheral blood mononuclear cells (PBMCs) with human chorionic gonadotropin (hCG) prior to uterine introduction, (ii) administering those PBMCs into the uterus at least two months before embryo transfer, where the embryo is derived from oocytes retrieved at least two months before transfer, and (iii) requiring pregnancy/implantation probability improvement versus IVF lacking at least one of the “(a)+(b)” steps. Dependent claims tighten timing (two cycles or ovulations; 2–12 months oocyte retrieval windows), add embryo transfer medium constraints (inception-promoting agent as soluble HLA-G at an optical density window), and include PBMC collection timing and multi-portion PBMC dosing.

Patent landscape impact: the estate is likely to be attacked on (a) obviousness over existing immunomodulatory/autologous PBMC or immune-cell uterine transfer literature and (b) indefiniteness/enablement around “increase in probability” and assay-defined sHLA-G optical density. For commercial freedom-to-operate, the key risk is that claim coverage turns less on the embryo lab steps and more on (i) PBMC preparation with hCG, (ii) uterine PBMC timing relative to embryo transfer (≥2 months), and (iii) the “no controlled ovarian stimulation” scenarios embedded in dependent claims.

Critical note: a complete, accurate “claim chart,” prosecution history read-through, and freedom-to-operate landscape requires the actual published patent document text and citation set (specifically: independent claim numbering as published, definitions, specification embodiments, and the cited art). The prompt provides only the claim set you pasted. Without the underlying patent publication record, no reliable mapping to specific cited prior art, examiner rationale, terminal disclaimer terms, or claim construction can be produced.

What are the key independent claims in US 10,271,876 and what do they require for infringement?

Claim 1: the core infringement hook

Claim 1 is structured as a method of IVF for a female patient with two compulsory operational pillars and multiple parameter constraints:

1. Uterine introduction of PBMCs

   • Introducing an effective amount of a composition comprising peripheral blood mononuclear cells into the uterus.

2. Embryo origin and timing synchronization

   • Transferring at least one embryo derived from at least one oocyte retrieved at least two months prior to embryo transfer.

3. PBMC pre-conditioning

   • Prior to uterine PBMC introduction, at least a portion of PBMCs were cultured in the presence of human chorionic gonadotropin.

4. PBMC collection timing

   • PBMCs are derived from blood collected by the patient at a first time between:
     • embryo transfer date, and
     • three days prior to embryo transfer.

5. Outcome-driven limitation

   • The method “results in an increase in probability of implantation… with successful inception of pregnancy” compared to IVF methods lacking at least one of steps (a) and (b).

Claim 14: alternative framing with step-by-step process chronology

Claim 14 is effectively a complementary independent claim that:

• initiates ovulation to obtain oocytes,
• obtains PBMCs,
• fertilizes to create embryos,
• introduces PBMCs into uterus at least two months after (a),
• introduces embryo after PBMC introduction.

It also embeds:

• hCG-culturing of at least a portion of PBMCs before uterine introduction, and
• PBMC collection at most three days before embryo introduction.

Practical implication: you can infringe via either claim theory depending on how the process is described/documented. In litigation, the party’s protocol records (collection date, PBMC culture conditions, uterine dosing timing, and embryo transfer date) become central.

How does the hCG-cultured PBMC uterine timing (≥2 months) shape patent scope?

The strongest scope-defining elements are the temporal couplings:

• PBMC collection is close to embryo transfer (≤3 days prior).
• PBMC uterine introduction occurs ≥2 months after oocyte retrieval/ovulation in claim 14, and at least two months before embryo transfer in claim 1’s logic.
• Embryo derived from oocytes retrieved ≥2 months before embryo transfer.

This means the method is not just “immune cells + IVF.” It is a scheduled immune conditioning interval where the immunologic composition is introduced into the uterus long enough before embryo transfer to plausibly modulate implantation readiness.

Why that matters for design-around

A competitor can reduce risk by altering at least one of:

• removing hCG from the PBMC culture step,
• changing uterine PBMC administration timing so it is <2 months pre-transfer,
• using oocytes retrieved less than two months prior to embryo transfer,
• collecting PBMCs outside the “between transfer and three days prior” window,
• changing inception-promoting agent approach (if relying on the dependent claims with sHLA-G OD constraints).

Which dependent claims add numeric precision (timing windows and sHLA-G optical density)?

Two-cycle / ovulation-based requirement (Claim 3)

Claim 3 requires the two-month embryo timeline corresponds to:

• at least two menstrual cycles, or
• two cycles of ovulation.

This narrows the patient scheduling interpretation: a fixed calendar two months may not satisfy a “two cycles” framing if cycles are irregular.

Oocyte retrieval windows (Claims 8–10)

• Claim 8: oocyte retrieved 2 to 12 months prior to embryo transfer.
• Claim 10: oocyte retrieved 3 to 12 months prior.

Controlled ovarian stimulation exclusions (Claims 9, 11, 17, 19)

Multiple dependents exclude protocols where controlled ovarian stimulation occurred during the pre-transfer window:

• Claims 9 and 11: no controlled ovarian stimulation during the relevant two-month interval.
• Claims 17 and 19: no controlled ovarian stimulation during the two-to-twelve-month interval (as framed by claim 14’s structure).

Scope effect: these dependents are important because they may capture specific clinical practices used by certain innovators while leaving “stimulated cycle” protocols outside coverage.

Embryo transfer medium and sHLA-G OD (Claims 4–6)

• Claim 4: embryo transferred in embryo transfer medium comprising an inception-promoting agent.
• Claim 5: inception-promoting agent is soluble HLA-G (sHLA-G) with concentration range 0.175–0.350 OD, with OD defined as optical density measured at 400–450 nm.
• Claim 6: embryos cultured in the embryo transfer medium for 5 min to 20 min immediately prior to transfer.

Scope effect: this adds a laboratory assay-dependent constraint. It can be a powerful infringement lever when a sponsor’s formulation uses exactly that sHLA-G concentration expressed in OD units and the same absorbance measurement parameters.

Design-around angle:

• use a different inception-promoting agent,
• express concentration differently (if not mapping to the OD range),
• change the immediate pre-transfer exposure window (outside 5–20 min),
• avoid that medium step entirely.

PBMC portioning and split dosing logic (Claims 12–13, 20–21)

Claim 12 and Claim 20 add split dosing:

• first PBMC portion collected at a first time between transfer (or embryo introduction) and 3 days prior,
• second portion collected at a later time within the same general window, with the second after the first.

Claim 13 and Claim 21 tie the first portion to hCG-culturing.

This can matter in protocol variants that perform serial blood draws or staged uterine dosing.

What do the method claims implicitly require about cell identity and preparation?

The claims specify:

• “composition comprising PBMCs,”
• at least a portion cultured in presence of hCG,
• uterine introduction at an “effective amount.”

They do not, in the pasted claims, specify:

• PBMC enrichment method (e.g., Ficoll density gradient),
• culture duration, medium composition, concentration of hCG, viability thresholds,
• dosing volume/cell count,
• release criteria.

But infringement in practice will still require showing the administered material was PBMCs as claimed and that hCG-culturing occurred prior to uterine introduction. Protocol SOPs and batch records typically determine whether “at least a portion” of PBMCs underwent the claimed conditioning.

What is the patent’s likely enforceable focus: immunomodulation vs embryo lab technique?

Based on the claims, enforcement centers on uterine immunologic conditioning and timing architecture, not:

• fertilization method (conventional IVF vs ICSI),
• embryo culture duration (blastocyst vs cleavage stage) except as implied by embryo transfer timing,
• sperm handling,
• endometrium biopsy, uterine lavage, or other adjuncts (not in the claims you pasted).

Even the sHLA-G formulation limitation is in the embryo transfer medium context, not in the core PBMC preparation.

How strong is the patent estate for IVF PBMC-based implantation enhancement?

Strength factors (based on claim drafting)

• Multiple synchronized limitations create specific process fingerprints (PBMC hCG culture + uterine timing + oocyte retrieval timeline).
• Dependent claims add numeric parameters (sHLA-G OD range; 5–20 min embryo medium exposure).
• Outcome language (“increase in probability of implantation…”) can be used to support non-obviousness if tied to objective results in the specification.

Vulnerabilities (attack points aligned to typical US practice)

• Obviousness: immunologic approaches and autologous cell-based endometrial modulation are known in reproductive medicine. If the prior art includes PBMC uterine introduction and immunomodulation using gonadotropin/hCG-related cues, the combination may be argued as routine optimization.
• Unclear claim meaning from assay-dependent terms: sHLA-G concentration is expressed as OD at 400–450 nm. If measurement protocol, calibration, and conversion to actual mass/units are not tightly defined, indefiniteness and enablement arguments become plausible.
• “Increase in probability” as a limitation: outcome-based statements can be difficult to prove during infringement and can create eligibility/definiteness arguments depending on how the court construes whether the limitation is functional or comparative to “methods lacking at least one of (a) and (b).”

What prior art risk categories are most likely relevant, claim-by-claim?

Without the cited-art list from the patent document, only category-level risk can be mapped:

1. PBMC uterine introduction / immune cell transfer in IVF

   • Any prior art describing PBMC administration to modulate implantation would attack novelty and overlap with the “introducing PBMCs” element.

2. hCG as an immunomodulatory co-factor

   • Literature on hCG’s effects on immune cells (including cytokines and implantation-related pathways) could be used to argue that “culture PBMCs in hCG” is an obvious enhancement.

3. Timed uterine immune modulation during IVF cycles

   • Protocols that administer immunologic agents at defined windows around implantation would attack the “≥2 months” timing architecture, especially if multiple-cycle intervals are already known.

4. sHLA-G in implantation contexts

   • Any prior art around sHLA-G as an implantation-promoting molecule could attack dependent claim 5/6 if the OD range and assay conditions are either disclosed or would be predictable.

What litigation and FDA/Orange Book status matter for this patent?

The question set is method claims. These claims:

• typically do not map directly to an FDA drug approval or an Orange Book listing, because they are process claims tied to a clinical procedure rather than a marketed drug product.
• still can be implicated in litigation under Hatch-Waxman only indirectly if an associated product (e.g., an sHLA-G-containing medium) is separately approved and listed.

However, no Orange Book/FDA pathway information is provided in the prompt, and producing an accurate Orange Book status or Paragraph IV analysis would require the patent’s publication record tied to a specific NDA/BLA or product.

What generic entry risks exist for competitors in this space?

Procedure-based entry risks

Because the claims are directed to a method of IVF (clinical procedure), “generic entry” is less about copying a drug label and more about:

• adopting the same PBMC collection and culture steps,
• delivering PBMCs into the uterus at the same lead time relative to embryo transfer,
• using the same sHLA-G embryo transfer medium when the dependent claims are asserted,
• matching patient selection constraints (e.g., no controlled ovarian stimulation windows for the dependent claim variants).

IP barriers

• The hCG-culturing step is a potential key barrier. If competitors avoid hCG in PBMC culture or avoid the defined PBMC timing windows, they can argue non-infringement.
• The OD-defined sHLA-G limitation can be used to cabin dependent claim coverage to a narrow formulation implementation.

How does this claimset compare with typical immune-cell IVF patent patterns?

Common patterns in reproductive immunology IP include:

• endometrial immune modulation using biologics,
• cytokine profiling-based selection,
• intrauterine injection of immune-cell fractions prepared for therapeutic effect,
• short pre-transfer manipulations.

The distinguishing feature here is the long interval architecture:

• PBMC collection is close to embryo transfer (within 3 days),
• but PBMC uterine introduction and oocyte-to-embryo temporal spacing are keyed to multi-month lead times (≥2 months and up to 12 months in dependents).

That pattern is more specific than many broad “immune modulation during IVF” filings and therefore may be narrower, but also more enforceable if a competitor’s clinical workflow matches the fingerprint.

Key Takeaways

• US 10,271,876 claims a targeted IVF workflow built around hCG-cultured autologous PBMCs and a ≥2-month uterine immune-conditioning window aligned to oocyte retrieval timing.
• Independent claim 1 and claim 14 differ in chronology framing, but both require: PBMCs cultured with hCG, PBMC uterine introduction, embryo transfer derived from oocytes retrieved ≥2 months prior, and PBMC collection occurring within a tight window relative to embryo transfer.
• Dependent claims add enforceability via cycle-based timing, controlled ovarian stimulation exclusions, sHLA-G embryo transfer medium with OD-defined concentration, and multi-part PBMC dosing.
• The main legal exposure for competitors is not “having immune-cell therapy,” but matching the exact temporal and preparation constraints. The main patent validity exposure is combination obviousness and assay-dependent parameter clarity (OD range) tied to sHLA-G.

FAQs

1. Does US 10,271,876 cover IVF protocols that use controlled ovarian stimulation in the pre-transfer interval?
   Coverage depends on whether the asserted claim is a dependent claim containing the “no controlled ovarian stimulation” limitations.

2. What is the infringement relevance of collecting PBMCs more than three days before embryo transfer?
   Independent claim 1 and claim 14 as pasted require PBMC collection within the “between transfer and 3 days prior” window.

3. Can competitors design around by culturing PBMCs without hCG?
   The pasted claims require that at least a portion of PBMCs were cultured in the presence of hCG prior to uterine introduction.

4. How does the sHLA-G optical density range limit dependent claim coverage?
   Dependent claims specify an OD value at 400–450 nm, plus an embryo incubation window in that medium.

5. Is “increase in probability of implantation” an outcome that must be proven for infringement?
   It is a claim limitation as pasted; how it is treated depends on claim construction and the evidence framework in the specific forum.

References (APA)

1. (No external sources were provided or citable from the prompt content.)

Details for Patent 10,271,876

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	January 15, 1974		2032-10-18
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	December 27, 1984		2032-10-18
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 15, 1985		2032-10-18